CN117756913A - Novel long-acting polypeptide compound, composition and application thereof - Google Patents
Novel long-acting polypeptide compound, composition and application thereof Download PDFInfo
- Publication number
- CN117756913A CN117756913A CN202310598335.7A CN202310598335A CN117756913A CN 117756913 A CN117756913 A CN 117756913A CN 202310598335 A CN202310598335 A CN 202310598335A CN 117756913 A CN117756913 A CN 117756913A
- Authority
- CN
- China
- Prior art keywords
- compound
- iva
- aib
- γglu
- egtftsdysi
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 170
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 144
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 115
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 113
- 239000000203 mixture Substances 0.000 title claims abstract description 15
- 150000001413 amino acids Chemical class 0.000 claims abstract description 62
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 22
- 239000003814 drug Substances 0.000 claims description 33
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 13
- 229940125877 compound 31 Drugs 0.000 claims description 13
- 208000008589 Obesity Diseases 0.000 claims description 11
- 229940127573 compound 38 Drugs 0.000 claims description 11
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 claims description 11
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 claims description 10
- 235000020824 obesity Nutrition 0.000 claims description 10
- HXMVNCMPQGPRLN-UHFFFAOYSA-N 2-hydroxyputrescine Chemical compound NCCC(O)CN HXMVNCMPQGPRLN-UHFFFAOYSA-N 0.000 claims description 8
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 claims description 5
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 claims description 5
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 claims description 5
- 229940126639 Compound 33 Drugs 0.000 claims description 5
- 229940127007 Compound 39 Drugs 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 claims description 4
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 2
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 claims description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 2
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 claims description 2
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 claims description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 2
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 claims description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 2
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 claims description 2
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 claims description 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 claims description 2
- OMBVEVHRIQULKW-DNQXCXABSA-M (3r,5r)-7-[3-(4-fluorophenyl)-8-oxo-7-phenyl-1-propan-2-yl-5,6-dihydro-4h-pyrrolo[2,3-c]azepin-2-yl]-3,5-dihydroxyheptanoate Chemical compound O=C1C=2N(C(C)C)C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C=3C=CC(F)=CC=3)C=2CCCN1C1=CC=CC=C1 OMBVEVHRIQULKW-DNQXCXABSA-M 0.000 claims description 2
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 claims description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 2
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 claims description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 claims description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 2
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 claims description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims description 2
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 claims description 2
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 claims description 2
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 claims description 2
- 229940126657 Compound 17 Drugs 0.000 claims description 2
- 125000000734 D-serino group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 claims description 2
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 claims description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims description 2
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 claims description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 2
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 claims description 2
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 229940125773 compound 10 Drugs 0.000 claims description 2
- 229940125797 compound 12 Drugs 0.000 claims description 2
- 229940126543 compound 14 Drugs 0.000 claims description 2
- 229940125758 compound 15 Drugs 0.000 claims description 2
- 229940126142 compound 16 Drugs 0.000 claims description 2
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 229940125810 compound 20 Drugs 0.000 claims description 2
- 229940126086 compound 21 Drugs 0.000 claims description 2
- 229940126208 compound 22 Drugs 0.000 claims description 2
- 229940125833 compound 23 Drugs 0.000 claims description 2
- 229940125961 compound 24 Drugs 0.000 claims description 2
- 229940125846 compound 25 Drugs 0.000 claims description 2
- 229940125851 compound 27 Drugs 0.000 claims description 2
- 229940127204 compound 29 Drugs 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims description 2
- 229940125878 compound 36 Drugs 0.000 claims description 2
- 229940125807 compound 37 Drugs 0.000 claims description 2
- 229940126540 compound 41 Drugs 0.000 claims description 2
- 229940125936 compound 42 Drugs 0.000 claims description 2
- 229940125844 compound 46 Drugs 0.000 claims description 2
- 229940127271 compound 49 Drugs 0.000 claims description 2
- 229940125898 compound 5 Drugs 0.000 claims description 2
- 229940126545 compound 53 Drugs 0.000 claims description 2
- 229940127113 compound 57 Drugs 0.000 claims description 2
- 229940125900 compound 59 Drugs 0.000 claims description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 2
- YCJZWBZJSYLMPB-UHFFFAOYSA-N n-(2-chloropyrimidin-4-yl)-2,5-dimethyl-1-phenylimidazole-4-carboxamide Chemical compound CC=1N(C=2C=CC=CC=2)C(C)=NC=1C(=O)NC1=CC=NC(Cl)=N1 YCJZWBZJSYLMPB-UHFFFAOYSA-N 0.000 claims description 2
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 2
- 238000010976 amide bond formation reaction Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 27
- 238000002474 experimental method Methods 0.000 abstract description 20
- 238000006467 substitution reaction Methods 0.000 abstract description 5
- 230000007062 hydrolysis Effects 0.000 abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 4
- 150000008574 D-amino acids Chemical class 0.000 abstract description 2
- 150000008575 L-amino acids Chemical class 0.000 abstract description 2
- 230000000857 drug effect Effects 0.000 abstract description 2
- 125000003275 alpha amino acid group Chemical group 0.000 abstract 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 82
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 68
- 239000008103 glucose Substances 0.000 description 68
- 239000008280 blood Substances 0.000 description 54
- 210000004369 blood Anatomy 0.000 description 41
- 235000001014 amino acid Nutrition 0.000 description 34
- 229940024606 amino acid Drugs 0.000 description 32
- 241000699670 Mus sp. Species 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- 229940079593 drug Drugs 0.000 description 23
- 239000011347 resin Substances 0.000 description 21
- 229920005989 resin Polymers 0.000 description 21
- 238000007410 oral glucose tolerance test Methods 0.000 description 19
- 238000012360 testing method Methods 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 15
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
- 239000000047 product Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 12
- DLSWIYLPEUIQAV-UHFFFAOYSA-N Semaglutide Chemical compound CCC(C)C(NC(=O)C(Cc1ccccc1)NC(=O)C(CCC(O)=O)NC(=O)C(CCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CCC(NC(=O)CCCCCCCCCCCCCCCCC(O)=O)C(O)=O)NC(=O)C(C)NC(=O)C(C)NC(=O)C(CCC(N)=O)NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(CC(C)C)NC(=O)C(Cc1ccc(O)cc1)NC(=O)C(CO)NC(=O)C(CO)NC(=O)C(NC(=O)C(CC(O)=O)NC(=O)C(CO)NC(=O)C(NC(=O)C(Cc1ccccc1)NC(=O)C(NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(C)(C)NC(=O)C(N)Cc1cnc[nH]1)C(C)O)C(C)O)C(C)C)C(=O)NC(C)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CCCNC(N)=N)C(=O)NCC(O)=O DLSWIYLPEUIQAV-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 150000001408 amides Chemical class 0.000 description 12
- 230000037396 body weight Effects 0.000 description 12
- 230000002218 hypoglycaemic effect Effects 0.000 description 12
- 229920001223 polyethylene glycol Polymers 0.000 description 12
- 229950011186 semaglutide Drugs 0.000 description 12
- 108010060325 semaglutide Proteins 0.000 description 12
- REITVGIIZHFVGU-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](COC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 REITVGIIZHFVGU-IBGZPJMESA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 241000700159 Rattus Species 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 239000002202 Polyethylene glycol Substances 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 238000010168 coupling process Methods 0.000 description 9
- 238000012986 modification Methods 0.000 description 9
- 230000004048 modification Effects 0.000 description 9
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- XVVOERDUTLJJHN-UHFFFAOYSA-N Lixisenatide Chemical compound C=1NC2=CC=CC=C2C=1CC(C(=O)NC(CC(C)C)C(=O)NC(CCCCN)C(=O)NC(CC(N)=O)C(=O)NCC(=O)NCC(=O)N1C(CCC1)C(=O)NC(CO)C(=O)NC(CO)C(=O)NCC(=O)NC(C)C(=O)N1C(CCC1)C(=O)N1C(CCC1)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)CC)NC(=O)C(NC(=O)C(CC(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(CCC(O)=O)NC(=O)C(CCC(O)=O)NC(=O)C(CCSC)NC(=O)C(CCC(N)=O)NC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)C(CC(O)=O)NC(=O)C(CO)NC(=O)C(NC(=O)C(CC=1C=CC=CC=1)NC(=O)C(NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)CNC(=O)C(N)CC=1NC=NC=1)C(C)O)C(C)O)C(C)C)CC1=CC=CC=C1 XVVOERDUTLJJHN-UHFFFAOYSA-N 0.000 description 8
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 8
- 108010004367 lixisenatide Proteins 0.000 description 8
- 229960001093 lixisenatide Drugs 0.000 description 8
- CNBUSIJNWNXLQQ-NSHDSACASA-N (2s)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CNBUSIJNWNXLQQ-NSHDSACASA-N 0.000 description 7
- MHSLDASSAFCCDO-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylpyrazol-3-yl)-3-(4-pyridin-4-yloxyphenyl)urea Chemical compound CN1N=C(C(C)(C)C)C=C1NC(=O)NC(C=C1)=CC=C1OC1=CC=NC=C1 MHSLDASSAFCCDO-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 7
- 230000008878 coupling Effects 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- -1 fmoc-Phe-OH Chemical compound 0.000 description 6
- 230000003914 insulin secretion Effects 0.000 description 6
- 239000006166 lysate Substances 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 5
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 5
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 5
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 5
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 5
- 238000003304 gavage Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 4
- 108090001061 Insulin Proteins 0.000 description 4
- 206010022489 Insulin Resistance Diseases 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 238000012790 confirmation Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229940125396 insulin Drugs 0.000 description 4
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 108091005601 modified peptides Proteins 0.000 description 4
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102100032882 Glucagon-like peptide 1 receptor Human genes 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 102100040918 Pro-glucagon Human genes 0.000 description 3
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 3
- 230000008827 biological function Effects 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 238000010241 blood sampling Methods 0.000 description 3
- 230000001808 coupling effect Effects 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000002473 insulinotropic effect Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000001543 one-way ANOVA Methods 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- FODJWPHPWBKDON-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 FODJWPHPWBKDON-IBGZPJMESA-N 0.000 description 2
- WDGICUODAOGOMO-DHUJRADRSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-5-oxo-5-(tritylamino)pentanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)CC(=O)NC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 WDGICUODAOGOMO-DHUJRADRSA-N 0.000 description 2
- LZOLWEQBVPVDPR-VLIAUNLRSA-N (2s,3r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]butanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H]([C@H](OC(C)(C)C)C)C(O)=O)C3=CC=CC=C3C2=C1 LZOLWEQBVPVDPR-VLIAUNLRSA-N 0.000 description 2
- NDKDFTQNXLHCGO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 NDKDFTQNXLHCGO-UHFFFAOYSA-N 0.000 description 2
- HCZMHWVFVZAHCR-UHFFFAOYSA-N 2-[2-(2-sulfanylethoxy)ethoxy]ethanethiol Chemical compound SCCOCCOCCS HCZMHWVFVZAHCR-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 2
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 2
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 2
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000644 isotonic solution Substances 0.000 description 2
- GCHPUFAZSONQIV-UHFFFAOYSA-N isovaline Chemical compound CCC(C)(N)C(O)=O GCHPUFAZSONQIV-UHFFFAOYSA-N 0.000 description 2
- 208000001921 latent autoimmune diabetes in adults Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- 238000004804 winding Methods 0.000 description 2
- ZPGDWQNBZYOZTI-SFHVURJKSA-N (2s)-1-(9h-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ZPGDWQNBZYOZTI-SFHVURJKSA-N 0.000 description 1
- ADOHASQZJSJZBT-SANMLTNESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]propanoic acid Chemical compound C12=CC=CC=C2N(C(=O)OC(C)(C)C)C=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ADOHASQZJSJZBT-SANMLTNESA-N 0.000 description 1
- JAUKCFULLJFBFN-VWLOTQADSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoic acid Chemical compound C1=CC(OC(C)(C)C)=CC=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JAUKCFULLJFBFN-VWLOTQADSA-N 0.000 description 1
- OTKXCALUHMPIGM-FQEVSTJZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 OTKXCALUHMPIGM-FQEVSTJZSA-N 0.000 description 1
- OJBNDXHENJDCBA-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-(prop-2-enoxycarbonylamino)hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OCC=C)C(=O)O)C3=CC=CC=C3C2=C1 OJBNDXHENJDCBA-QFIPXVFZSA-N 0.000 description 1
- UMRUUWFGLGNQLI-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UMRUUWFGLGNQLI-QFIPXVFZSA-N 0.000 description 1
- OYXZPXVCRAAKCM-SANMLTNESA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(1-tritylimidazol-4-yl)propanoic acid Chemical compound C1=NC(C[C@H](NC(=O)OC(C)(C)C)C(O)=O)=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 OYXZPXVCRAAKCM-SANMLTNESA-N 0.000 description 1
- ZEQLLMOXFVKKCN-AWEZNQCLSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(OC(C)(C)C)C=C1 ZEQLLMOXFVKKCN-AWEZNQCLSA-N 0.000 description 1
- BKYLRPNYYCFVHV-ZETCQYMHSA-N (2s)-5-amino-2-(4-aminobutylamino)-5-oxopentanoic acid Chemical compound NCCCCN[C@H](C(O)=O)CCC(N)=O BKYLRPNYYCFVHV-ZETCQYMHSA-N 0.000 description 1
- GOPWHXPXSPIIQZ-FQEVSTJZSA-N (4s)-4-(9h-fluoren-9-ylmethoxycarbonylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCC(O)=O)C(=O)OC(C)(C)C)C3=CC=CC=C3C2=C1 GOPWHXPXSPIIQZ-FQEVSTJZSA-N 0.000 description 1
- FVTVMQPGKVHSEY-UHFFFAOYSA-N 1-AMINOCYCLOBUTANE CARBOXYLIC ACID Chemical compound OC(=O)C1(N)CCC1 FVTVMQPGKVHSEY-UHFFFAOYSA-N 0.000 description 1
- RUVRGYVESPRHSZ-UHFFFAOYSA-N 2-[2-(2-azaniumylethoxy)ethoxy]acetate Chemical compound NCCOCCOCC(O)=O RUVRGYVESPRHSZ-UHFFFAOYSA-N 0.000 description 1
- 125000001431 2-aminoisobutyric acid group Chemical group [#6]C([#6])(N*)C(*)=O 0.000 description 1
- JUCDAUSILDWYOA-UHFFFAOYSA-N 20-[(2-methylpropan-2-yl)oxy]-20-oxoicosanoic acid Chemical compound CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(O)=O JUCDAUSILDWYOA-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 101150046735 LEPR gene Proteins 0.000 description 1
- 101150063827 LEPROT gene Proteins 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 238000010811 Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Methods 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000006229 amino acid addition Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000010036 cardiovascular benefit Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 238000011960 computer-aided design Methods 0.000 description 1
- 208000012696 congenital leptin deficiency Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000013118 diabetic mouse model Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 210000003158 enteroendocrine cell Anatomy 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- ZVHRTJHLSYKEAK-UHFFFAOYSA-N ethyl 2-[5-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-2-oxo-3,4-dihydroquinolin-1-yl]acetate Chemical compound CCOC(=O)CN1C(=O)CCC2=C1C=CC=C2OC1=NC(=CC(CN)=C1)C(F)(F)F ZVHRTJHLSYKEAK-UHFFFAOYSA-N 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 208000020694 gallbladder disease Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 208000004104 gestational diabetes Diseases 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 238000013227 male C57BL/6J mice Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- CEXCHYIGFUAPKW-UHFFFAOYSA-N methanol;piperidine Chemical compound OC.C1CCNCC1 CEXCHYIGFUAPKW-UHFFFAOYSA-N 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 208000001022 morbid obesity Diseases 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 150000003140 primary amides Chemical group 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 201000002859 sleep apnea Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention discloses a novel long-acting polypeptide compound, a composition and application thereof. The long-acting polypeptide compound of the invention enhances the stability, activity and hydrolysis resistance of the polypeptide by replacing amino acids at key specific sites. Through a large number of experiments, after the amino acid position 2 and/or 13 of the main peptide chain of the polypeptide compound is replaced by the unnatural amino acid Aib, iva or Cba, the stability, activity and hydrolysis resistance of the polypeptide molecule are obviously enhanced; substitution of amino acid positions 27 and/or 28 with L and/or D amino acids, respectively, also significantly enhances the activity of the polypeptide molecule. The long-acting polypeptide compound has long half-life period and good drug effect of treating diabetes and reducing weight.
Description
Technical Field
The invention belongs to the technical field of biochemistry, and particularly relates to a novel long-acting polypeptide compound, a composition and application thereof, wherein the novel long-acting polypeptide compound can be used for treating or preventing diabetes or obesity.
Background
Diabetes is a group of clinical syndromes caused by the interaction of genetic and environmental factors in which the body is at high blood glucose levels for a long period of time. Diabetes mellitus is manifested by absolute or relative inadequate insulin secretion and reduced sensitivity of target tissue cells to insulin, accompanied by a series of metabolic disorders of sugar, protein, fat, water, and electrolytes. The American Diabetes Association (ADA) of 2021 classified diabetes into four categories: type I diabetes, type II diabetes, gestational diabetes, and other specific types of diabetes. Wherein, the I-type diabetes accounts for 5-10% of all diabetics, the II-type diabetes accounts for about 90-95% of all diabetics. Type I diabetes is caused by destruction of autoimmune beta cells, often resulting in absolute insulin deficiency, including latent autoimmune diabetes in adults (LADA). Type II diabetics, on the basis of insulin resistance, gradually lose insulin secretion from the beta cells, have been called "non-insulin dependent diabetes mellitus" or "adult onset diabetes mellitus", and their remarkable pathophysiological characteristics are the decrease of insulin secretion caused by the decline of insulin glucose metabolism regulation (insulin resistance) accompanied by the defect of islet beta cell function; especially in the early stages of onset, insulin resistance is mainly caused by obesity, dyslipidemia, bad lifestyle and the like, and insulin secretion is relatively insufficient (Report of a WHO establishment.1999).
Diabetes is not easy to cure, and complications of diabetes bring great pain to patients, and usually need to take medicines for controlling blood sugar for life. In the field of diabetes treatment, these decades have progressed very rapidly, and in the field of non-insulin drugs, GLP-1 receptor agonists and analogues thereof have been applied clinically, with very large changes in clinical treatment and outcome (Frontiers in Endocrinology,2019, 10:155). It has been reported that: GLP-1 is an insulinotropic agent secreted by intestinal L cells and has pharmacological effects of promoting insulin secretion, inhibiting glucagon release, stimulating islet B cell regeneration, improving insulin sensitivity, increasing glucose utilization and the like (modern medicine and clinic, 2020.). Clinical studies have shown that type II diabetics, which exhibit impaired "incretin insulinotropic effect", have no significant impairment of their insulin secretion promoting and hypoglycemic effects. Therefore, GLP-1 and related receptors thereof have been clinically studied as important targets for the treatment of type II diabetes in the field of diabetes treatment, and have shown a strong and wide application prospect in the field of diabetes treatment (GLP-1 receptor agonist clinical application expert guidance opinion: chinese journal of diabetes, 2018, 26 (05): 353-361).
To date, many drugs have been marketed for GLP-1 receptor agonists (GLP-1 RA) and their related multi-target agonists, and clinical use has been over 10 years from the initial twice daily dosing to the last once a week, with a significant accumulation of clinical evidence for blood glucose reduction, cardiovascular benefit, and weight loss. With the marketing of weekly preparations, the preparation is greatly convenient for patients. At the same time, the medicine has good effect on the treatment of cardiovascular diseases and also promotes the acceptance of the medicines in recent years. However, it is notable that The currently marketed GLP-1 receptor and its associated target drugs also exhibit considerable toxic side effects and deficiencies, such as severe gastrointestinal reactions, nausea, vomiting, still a significant decrease in The frequency of administration by injection, etc. (The Lancet,2009,374 (9683):39-47.).
The ultra-long-acting polypeptide drug molecule modification technology is the key of research and development in the field and is a bottleneck to be broken through internationally. Therefore, how to further design and improve the hypoglycemic effect, reduce toxic and side effects, improve the duration of efficacy and/or half-life of the compounds is still an important technical problem to be solved by the skilled person, has significant social and clinical demands-!
Disclosure of Invention
In view of the above problems, an object of the present invention is to provide a novel long-acting polypeptide compound.
It is another object of the present invention to provide a composition comprising the above-described long-acting polypeptide compound.
It is a further object of the present invention to provide the use of the above long acting polypeptide compounds.
The amino acid sequence of the long-acting polypeptide compound according to the specific embodiment of the invention is as follows:
X1-X2-X3-GTFTSDYSI-X13-LDKIAQ-X20-AFVQWL-X27-X28-GGPSSG-X35-PPPS-R 1 ;
wherein, X3 is selected from E, Q or N; x27 is selected from L or I; x28 is selected from A or D; x35 is selected from A or Aib; x20 is K, K (G) x (SG) Z -γGlu-CO(CH 2 ) a CO 2 H)、K((PEG 2 ) b -γGlu-CO(CH 2 ) c CO 2 H) Or K ((AEEA) d -γGlu-CO(CH 2 ) e CO 2 H) Wherein x is an integer of 0 to 5, z is an integer of 1 to 5, a is an integer of 12 to 20, b is an integer of 1 to 8, c is an integer of 12 to 20, d is an integer of 1 to 8, and e is an integer of 12 to 20; r is R 1 Selected from OH or NH 2 ;
When X2 is selected from Aib, iva or Cba: x1 is selected from H or Y; x13 is selected from Aib, iva or Cba;
when X2 is D-Ser: x1 is H; x13 is selected from Aib, iva or Cba.
Preferably, when X20 is selected from K (G x (SG) Z -γGlu-CO(CH 2 ) a CO 2 H)、
K((PEG 2 ) b -γGlu-CO(CH 2 ) c CO 2 H) Or K ((AEEA) d -γGlu-CO(CH 2 ) e CO 2 H) In the time-course of which the first and second contact surfaces,
G x (SG) Z -γGlu-CO(CH 2 ) a CO 2 H、(PEG 2 ) b -γGlu-CO(CH 2 ) c CO 2 h or (AEEA) d -γGlu-CO(CH 2 ) e CO 2 H is a side arm structure of the long-acting polypeptide compound, and the side arm structure is connected with the main peptide chain of the long-acting polypeptide compound through an amide bond formed by the side arm structure and a side chain amino group of an amino acid K on the main peptide chain of the long-acting polypeptide compound.
Preferably, amino acid D at position 9 and amino acid K at position 16 on the long-acting polypeptide compound are connected through an amide bond.
Preferably, the long acting polypeptide compound, X20 is K (G x (SG) Z -γGlu-CO(CH 2 ) a CO 2 H) Where x is 2, z is 2 or 3, and a is 16 or 18.
Preferably, the long acting polypeptide compound, X20 is K ((PEG) 2 ) b -γGlu-CO(CH 2 ) c CO 2 H) Wherein b is 2 and c is 16 or 18.
Preferably, the long acting polypeptide compound, X20 is K ((AEEA) d -γGlu-CO(CH 2 ) e CO 2 H) Where d is 2 and e is 16 or 18.
Preferably, the long acting polypeptide compound, X35 is a.
Preferably, the long-acting polypeptide compound, X1 is Y, X2 is selected from Aib, iva or Cba, X3 is E, and X13 is selected from Aib, iva or Cba.
Preferably, the long-acting polypeptide compound, X2 is Iva and X13 is Aib or Iva; alternatively, X2 is Aib and X13 is Iva.
Preferably, the long-acting polypeptide compound, X1 is H, X2 is selected from Aib, iva or Cba, X3 is selected from E or Q; x13 is selected from Aib, iva or Cba.
Preferably, the long-acting polypeptide compound, X2 is Aib or Iva and X13 is Iva.
Preferably, the long-acting polypeptide compound, X2 is Aib and X1 is Y; x3 is E; x13 is selected from Iva or Cba; x27 is selected from L or I; x28 is selected from A or D; x35 is A.
Preferably, the long-acting polypeptide compound, X2 is selected from Iva or Cba, and X1 is Y; x3 is E; x13 is selected from Aib, iva or Cba; x27 is selected from L or I; x28 is selected from A or D; x35 is A.
Preferably, the long-acting polypeptide compound, X2 is selected from Aib, iva or Cba, and X1 is H; x3 is selected from E or Q; x13 is selected from Aib, iva or Cba; x27 is selected from L or I; x28 is selected from A or D; x35 is A.
Preferably, the long-acting polypeptide compound, X2 is Aib and X1 is Y; x3 is E; x13 is Iva; x20 is K (G) x (SG) Z -γGlu-CO(CH 2 ) a CO 2 H) Wherein x is 2, z is 2 or 3, a is 16 or 18; x27 is selected from L or I; x28 is selected from A or D; x35 is A.
Preferably, the long-acting polypeptide compound, X2 is Iva and X1 is Y; x3 is E; x13 is selected from Aib or Iva; x20 is K (G) x (SG) Z -γGlu-CO(CH 2 ) a CO 2 H) Wherein x is 2, z is 2 or 3, a is 16 or 18; x27 is selected from L or I; x28 is selected from A or D; x35 is A.
Preferably, the long-acting polypeptide compound, X2 is selected from Aib or Iva, and X1 is H; x3 is selected from E or Q; x13 is Iva; x20 is K (G) x (SG) Z -γGlu-CO(CH 2 ) a CO 2 H) Wherein x is 2, z is 2 or 3, a is 16 or 18; x27 is selected from L or I; x28 is selected from A or D; x35 is A.
Preferably, the long-acting polypeptide compound is selected from any one of the following compounds:
compound 1 (SEQ ID No. 1):
Y-Aib-QGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSG-Aib-PPPS-OH;
compound 2 (SEQ ID No. 2):
Y-Aib-QGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH;
compound 3 (SEQ ID No. 3):
Y-Aib-EGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH;
compound 4 (SEQ ID No. 4):
Y-Iva-EGTFTSDYSI-Aib-LDKIAQKAFVQWLIAGGPSSGAPPPS-OH;
compound 5 (SEQ ID No. 5):
Y-Aib-EGTFTSDYSI-Iva-LDKIAQKAFVQWLIAGGPSSGAPPPS-OH;
compound 6 (SEQ ID No. 6):
Y-Iva-EGTFTSDYSI-Iva-LDKIAQKAFVQWLIAGGPSSGAPPPS-OH; compound 7 (SEQ ID No. 7):
Y-Iva-EGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 8 (SEQ ID No. 8):
Y-Aib-EGTFTSDYSI-Iva-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 9 (SEQ ID No. 9):
Y-Iva-EGTFTSDYSI-Iva-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 10 (SEQ ID No. 10):
Y-Iva-QGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 11 (SEQ ID No. 11):
Y-Cba-EGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 12 (SEQ ID No. 12):
Y-Cba-EGTFTSDYSI-Iva-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 13 (SEQ ID No. 13):
Y-Aib-EGTFTSDYSI-Cba-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 14 (SEQ ID No. 14):
Y-Iva-EGTFTSDYSI-Cba-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 15 (SEQ ID No. 15):
H-Aib-EGTFTSDYSI-Aib-LDKIAQKAFVQWLLAGGPSSGAPPPS-OH; compound 16 (SEQ ID No. 16):
H-Iva-QGTFTSDYSI-Aib-LDKIAQKAFVQWLLAGGPSSGAPPPS-OH; compound 17 (SEQ ID No. 17):
H-Iva-EGTFTSDYSI-Iva-LDKIAQKAFVQWLLAGGPSSGAPPPS-OH;
compound 18 (SEQ ID No. 18):
H-Iva-QGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH;
compound 19 (SEQ ID No. 19):
H-Iva-EGTFTSDYSI-Iva-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH;
compound 20 (SEQ ID No. 20):
H-Cba-QGTFTSDYSI-Aib-LDKIAQKAFVQWLIAGGPSSGAPPPS-OH;
compound 21 (SEQ ID No. 21):
H-Cba-QGTFTSDYSI-Iva-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH;
compound 22 (SEQ ID No. 22):
H-(D-Ser)-QGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH;
compound 23 (SEQ ID No. 23):
Y-Iva-EGTFTS(D)YSI-Iva-LD(K)IAQKAFVQWLIAGGPSSGAPPPS-OH, wherein amino acid D at position 9 is linked to amino acid K at position 16 by an amide bond;
Compound 24 (SEQ ID No. 24):
Y-Aib-EGTFTS(D)YSI-Iva-LD(K)IAQKAFVQWLLDGGPSSGAPPPS-OH, wherein amino acid D at position 9 is linked to amino acid K at position 16 by an amide bond;
compound 25 (SEQ ID No. 25):
Y-Iva-EGTFTS(D)YSI-Iva-LD(K)IAQKAFVQWLLDGGPSSGAPPPS-OH, wherein amino acid D at position 9 is linked to amino acid K at position 16 by an amide bond;
compound 26 (SEQ ID No. 26):
H-Aib-QGTFTS(D)YSI-Aib-LD(K)IAQKAFVQWLLDGGPSSGAPPPS-OH, wherein amino acid D at position 9 is linked to amino acid K at position 16 by an amide bond;
compound 27 (SEQ ID No. 27):
H-Iva-EGTFTS(D)YSI-Aib-LD(K)IAQKAFVQWLLDGGPSSGAPPPS-OH, wherein amino acid D at position 9 is linked to amino acid K at position 16 by an amide bond;
compound 28 (SEQ ID No. 28):
Y-Aib-QGTFTSDYSI-Aib-LDKIAQK(GGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLDGGPSSG-Aib-PPPS-NH 2 ;
compound 29 (SEQ ID No. 29):
Y-Aib-QGTFTSDYSI-Aib-LDKIAQK(GGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLDGGPSSGAPPPS-NH 2 ;
compound 30 (SEQ ID No. 30):
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK(GGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLDGGPSSGAPPPS-NH 2 ;
compound 31 (SEQ ID No. 31):
Y-Iva-EGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIAGGPSSGAPPPS-NH 2 ;
compound 32 (SEQ ID No. 32):
Y-Iva-EGTFTSDYSI-Aib-LDKIAQK(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIAGGPSSGAPPPS-NH 2 ;
compound 33 (SEQ ID No. 33):
Y-Aib-EGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIAGGPSSGAPPPS-NH 2 ;
compound 34 (SEQ ID No. 34):
Y-Aib-EGTFTSDYSI-Iva-LDKIAQK(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIAGGPSSGAPPPS-NH 2 ;
compound 35 (SEQ ID No. 35):
Y-Iva-EGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIAGGPSSGAPPPS-NH 2 ;
compound 36 (SEQ ID No. 36):
Y-Iva-EGTFTSDYSI-Iva-LDKIAQK(AEEA-AEEA-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIAG GPSSGAPPPS-NH 2 ;
compound 37 (SEQ ID No. 37):
Y-Iva-EGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLD GGPSSGAPPPS-NH 2 ;
compound 38 (SEQ ID No. 38):
Y-Aib-EGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLD GGPSSGAPPPS-NH 2 ;
compound 39 (SEQ ID No. 39):
Y-Iva-EGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLD GGPSSGAPPPS-NH 2 ;
compound 40 (SEQ ID No. 40):
Y-Iva-QGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLD GGPSSGAPPPS-NH 2 ;
compound 41 (SEQ ID No. 41):
Y-Cba-EGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLL DGGPSSGAPPPS-NH 2 ;
compound 42 (SEQ ID No. 42):
Y-Cba-EGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLL DGGPSSGAPPPS-NH 2 ;
compound 43 (SEQ ID No. 43):
Y-Aib-EGTFTSDYSI-Cba-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLL DGGPSSGAPPPS-NH 2 ;
compound 44 (SEQ ID No. 44):
Y-Iva-EGTFTSDYSI-Cba-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLL DGGPSSGAPPPS-NH 2 ;
compound 45 (SEQ ID No. 45):
H-Aib-EGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLA GGPSSGAPPPS-OH;
Compound 46 (SEQ ID No. 46):
H-Iva-EGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLA GGPSSGAPPPS-OH;
compound 47 (SEQ ID No. 47):
H-Iva-QGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLA GGPSSGAPPPS-OH;
compound 48 (SEQ ID No. 48):
H-Iva-EGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLA GGPSSGAPPPS-OH;
compound 49 (SEQ ID No. 49):
H-Iva-QGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLD GGPSSGAPPPS-OH;
compound 50 (SEQ ID No. 50):
H-Iva-EGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLD GGPSSGAPPPS-OH;
compound 51 (SEQ ID No. 51):
H-Cba-QGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLI AGGPSSGAPPPS-OH;
compound 52 (SEQ ID No. 52):
H-Cba-QGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLDGGPSSGAPPPS-OH;
compound 53 (SEQ ID No. 53):
H-Aib-QGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIAGGPSSG-Aib-PPPS-OH;
compound 54 (SEQ ID No. 54):
H-(D-Ser)-QGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLDGGPSSGAPPPS-OH;
compound 55 (SEQ ID No. 55):
Y-Iva-EGTFTS(D)YSI-Iva-LD(K)IAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIAGGPSSGAPPPS-NH 2 wherein amino acid D at position 9 and amino acid K at position 16 are connected through an amide bond;
compound 56 (SEQ ID No. 56):
Y-Aib-EGTFTS(D)YSI-Iva-LD(K)IAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLDGGPSSGAPPPS-NH 2 wherein amino acid D at position 9 and amino acid K at position 16 are connected through an amide bond;
compound 57 (SEQ ID No. 57):
Y-Iva-EGTFTS(D)YSI-Iva-LD(K)IAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLDGGPSSGAPPPS-NH 2 wherein amino acid D at position 9 and amino acid K at position 16 are connected through an amide bond;
compound 58 (SEQ ID No. 58):
H-Aib-QGTFTS(D)YSI-Aib-LD(K)IAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 h) AFVQWLLDGGPSSGAPPPS-OH, wherein amino acid D at position 9 is linked to amino acid K at position 16 by an amide bond;
compound 59 (SEQ ID No. 59):
H-Iva-EGTFTS(D)YSI-Aib-LD(K)IAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 h) AFVQWLLDGGPSSGAPPPS-OH, wherein amino acid D at position 9 is linked to amino acid K at position 16 by an amide bond;
compound 60 (SEQ ID No. 60):
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIA GGPSSGAPPPS-NH 2 。
C-terminal-NH in the Compounds of the invention 2 The terminal amino acid is aminated into a C-terminal primary amide, and the C-terminal-OH in the compound is the structure of the terminal amino acid.
Preferably, the long-acting polypeptide compound is a pharmaceutically acceptable salt.
The preparation method of the series of long-acting polypeptide compounds comprises the following steps:
step 1: and synthesizing main peptide resin corresponding to the main peptide chain of the polypeptide analogue according to Fmoc/t-Bu strategy.
Step 2: based on the main peptide resin, coupling a corresponding side arm structure according to Fmoc/t-Bu strategy to obtain a corresponding polypeptide resin; wherein the method comprises the steps ofThe structure of the side arm is PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 18 CO 2 H、AEEA-AEEA-γGlu-CO(CH 2 ) 18 CO 2 H、GGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H or GGSGSGSG-gamma Glu-CO (CH 2 ) 18 CO 2 H。
Step 3: adding a cracking solution into the polypeptide resin, performing a cracking reaction, removing the full protection of the polypeptide, and extracting a crude compound; purifying the crude compound.
According to the preparation method of the compounds 31, 35 and 38 in the specific embodiment of the invention, in the step 2, the coupling agent used is 1-hydroxybenzotriazole (HOBt) and N, N-Diisopropylcarbodiimide (DIC), the solvent is N, N-Dimethylformamide (DMF), and Fmoc groups are removed by 20% Piperidine (Pieridine)/N, N-dimethylformamide solution; in step 3, the lysate is prepared from trifluoroacetic acid (TFA), 2' - (1, 2-ethanediyl dioxy) diethyl mercaptan (DODT), m-cresol, H 2 The volume ratio of O is 92.5:2.5:2.5: 2.5; the crude compound extraction mode comprises filtration, precipitation and/or methyl tertiary butyl ether extraction. The purity of the obtained compounds 31, 35 and 38 is more than 96 percent.
It is a further object of the present invention to provide a composition comprising a long-acting polypeptide compound, and further comprising a pharmaceutically acceptable carrier or adjuvant. For example, carriers capable of reducing degradation and loss of drugs, reducing side effects, such as carriers for micelles, microemulsions, gels, and the like; adjuvants refer to materials added to make the drug into a suitable dosage form, such as buffers, lyophilization excipients, and the like, to enable the pharmaceutical compositions containing the compounds of the invention to be prepared as solutions or lyophilized powders for parenteral administration, which may be reconstituted by the addition of appropriate solvents or other pharmaceutically acceptable carriers prior to use, liquid formulations typically being buffers, isotonic solutions, and aqueous solutions. The buffer solution can be phosphate buffer solution, and the isotonic solution can be 0.9% sodium chloride solution, and the aqueous solution is directly obtained by dissolving with purified water.
It will be appreciated by those skilled in the art that the pharmaceutical compositions comprising the long-acting polypeptide compounds as active ingredient in combination with pharmaceutically acceptable carriers and/or excipients are suitable for various modes of administration, such as oral, transdermal, intravenous, intramuscular, topical, nasal, etc. Depending on the mode of administration employed, the pharmaceutical compositions of the present invention may be formulated in a variety of suitable dosage forms comprising at least one effective dose of a compound of the present invention and at least one pharmaceutically acceptable pharmaceutical carrier. Examples of suitable dosage forms are tablets, capsules, sugar-coated tablets, granules, oral solutions and syrups, ointments and patches for skin surfaces, aerosols, nasal sprays, and sterile solutions for injection.
The amount of the pharmaceutical composition of the present invention may vary widely and may be determined by one skilled in the art based on objective factors such as the kind of disease, the severity of the disease, the weight of the patient, the dosage form, the route of administration, etc.
It is also an object of the present invention to provide the use of long acting polypeptide compounds and compositions.
The invention obtains a series of long-acting polypeptide compounds, and develops and researches the pharmacodynamic effect of the series of medicines. The research shows that the long-acting polypeptide compound has longer half-life period, insulinotropic activity and no adverse reaction, can be used for treating diabetes and obesity, and can be potentially used as a new-generation medicament for treating diabetes and obesity.
The application of the long-acting polypeptide compound and the composition of the invention specifically comprises the following steps:
in the preparation of medicaments for preventing or treating diabetes mellitus, and in the preparation of medicaments for preventing or treating obesity.
The innovative results and beneficial effects of the invention:
the solution of the half-life and stability of the polypeptide is the key whether the design of the polypeptide medicine can be made into medicines or not, and is a major scientific and core problem of the research in the field. Wherein, the substitution of amino acids at key specific sites enhances the stability, activity and hydrolysis resistance of the polypeptide. Through a large number of experiments, after the amino acid position 2 and/or 13 of the main peptide chain of the polypeptide compound is replaced by the unnatural amino acid Aib, iva or Cba, the stability, activity and hydrolysis resistance of the polypeptide molecule are obviously enhanced; substitution of amino acid positions 27 and/or 28 with L and/or D amino acids, respectively, also significantly enhances the activity of the polypeptide molecule. The key findings for developing innovative polypeptide drugs are based on a large number of experimental growths (please see the specific examples). Besides innovation of main peptide chain, development of a super-long-acting polypeptide drug molecule modification technology is also key, and is a bottleneck to be broken through internationally in the field. The invention develops a site-specific side chain modification technology through bioinformatics, structural biology, computer aided design, structure-activity relationship research and the like, breaks through a super-long-acting polypeptide and protein drug molecule modification technology, greatly prolongs the half-life of the synthesized compound, and realizes super-long-acting of the polypeptide drug. The polypeptide compound disclosed by the invention not only has a primary structure, but also has a secondary/tertiary structure which is important for the activity of the polypeptide compound. Each protein/polypeptide has a specific secondary/tertiary spatial conformation which in turn is associated with their specific biological function, with a high degree of structural and functional uniformity; the secondary and tertiary spatial structures have a great influence on whether the compound can bind to the target, in what way the compound binds to the target and on the strength of the binding, i.e. the secondary/tertiary structure is crucial for the biological function of the polypeptide compound. The addition of the side chains greatly influences the secondary and tertiary space structures of the polypeptide compound, so that in the invention, the spatial conformation of the main peptide chain of the polypeptide compound is greatly changed by the addition of different side chains, the biological function of the polypeptide can be exerted by the change of the polypeptide conformation, the biological property of the polypeptide is unpredictable, and whether the polypeptide is effective for the long-acting of specific polypeptide or protein can be known by carrying out a large number of biological efficacy tests and experiments.
The novel long-acting polypeptide compound is designed and synthesized and the applied long-acting modification technology is effective only for the polypeptide compound or the uncertain polypeptide compound, has unpredictability, and is shown as a result of a test (example 6) for further verifying the creativity and novelty of the invention, the long-acting polypeptide compound greatly prolongs the half life, the medicine half life of rats can reach more than 22 hours, the super long-acting of polypeptide medicines is realized, and the frequency of one-time administration for 2 weeks or more for human use can be realized. The currently reported drug half-life of the polypeptide drug rats in the field is basically less than 10 hours, and only one-time dosing frequency of 1 week can be achieved.
The side chain modification technology of the application has no universal applicability, and whether the side chain modification technology is effective for long-acting of specific polypeptides or proteins under the condition of keeping activity or not can be known only by developing a great number of innovative biological efficacy tests and experiments. To illustrate this, we have also synthesized the following control compounds, compound 61 being a similar compound, compound 62 being the marketed polypeptide GLP-1 drug Lixisenatide (Lixisenatide), compound 63 and compound 64 being compounds obtained by modifying different positions of Lixisenatide with side chains, respectively:
Compound 61 (SEQ ID No. 61):
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK(AEEA-AEEA-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIAG GPSSGAPPPS-NH 2 ;
compound 62 (SEQ ID No. 62):
HGEGTFTSDLSKQMEEEVRLFIEWLKNGGPSSGAPPSKKKKKK-OH;
compound 63 (SEQ ID No. 63):
HGEGTFTSDLSK(GGSGSGSG-γGlu-CO(CH 2 )1 8 CO 2 H)QMEEEVRLFIEWLKNGGPS SGAPPSKKKKKK-OH;
compound 64 (SEQ ID No. 64):
HGEGTFTSDLSKQMEEEVRLFIEWLK(GGSGSGSG-γ-Glu-CO(CH 2 ) 18 CO 2 H)NGGP SSGAPPSKKKKKK-OH;
C-terminal-NH of Compound 61 2 Meaning that the terminal amino acid is amidated, the-OH at the C-terminus of compounds 62-64 is the terminal amino acid self-structure.
We have found that: rixilapide binds to the extracellular domain and transmembrane pocket of GLP-1R and forms a suitable steric hindrance with the GLP-1R receptor. The two modified peptides (compounds 63 and 64) form larger steric hindrance with GLP-1R due to the winding of a long-acting side chain, and the ligand-receptor binding is hindered, so that the modified peptides only show the winding and binding with the extracellular domain of GLP-1R, but have no binding site in a transmembrane pocket, so that the hypoglycemic effect of the modified peptides is not prolonged, and the original parent peptide loses the hypoglycemic effect. Our activity test (example 5) results show that: rixilapide is only modified by a side chain, and cannot improve glucose tolerance, and the effect of reducing blood sugar is greatly reduced or even inactivated. Therefore, the compound with brand new activity obtained by autonomous design, transformation and synthesis and screening through a series of activity verification tests of cell models and animal models is original.
The novel long-acting polypeptide compound of the present invention utilizes lipophilic substituents to bind albumin in blood, protecting it from enzymatic degradation, thereby increasing half-life. By stabilizing the helical structure of the molecule through intramolecular bridges, the potency and/or selectivity towards the target is improved.
The novel long-acting polypeptide compound has high synthesis yield, good stability, easy amplified production and low cost.
Meanwhile, the novel long-acting polypeptide compound of the present invention has a better effect of reducing body weight, and the long-acting polypeptide compound can be used for preventing body weight from growing or promoting body weight loss by causing food intake to be reduced and/or energy consumption to be increased, so that the novel long-acting polypeptide compound of the present invention can also be used for directly or indirectly treating other diseases caused by or characterized by overweight, such as treating and/or preventing obesity, morbid obesity, obesity-related inflammation, obesity-related gallbladder diseases, sleep apnea caused by obesity, and the effect of the present invention in these diseases can be due to the effect of the novel long-acting polypeptide compound directly or indirectly on body weight, or on other aspects of the body than body weight.
The abbreviations used in the present invention have the following specific meanings:
DCM is dichloromethane; DMF is N, N-dimethylformamide; meOH is methanol; piperidine is Piperidine; HOBt is 1-hydroxyBenzotriazole; DIC is N, N' -diisopropylcarbodiimide; fmoc is fluorenylmethoxycarbonyl; resin; FBS is fetal bovine serum; H. his is histidine; y, tyr is tyrosine; E. glu is glutamic acid; q, gln is glutamine; n, asn is asparagine; G. gly is glycine; t, thr is threonine; F. phe is phenylalanine; s, ser is serine; D. asp is aspartic acid; I. IIe is isoleucine; l, leu is leucine; K. lys is lysine; A. ala is alanine; v, val is valine; w, trp is tryptophan; p, pro is proline; aib is 2-aminoisobutyric acid; iva (Isovaline) is isovaline; cba (1-Aminocyclobutanecarboxylic acid) is alpha-amino cyclobutanoic acid; alloc is allyloxycarbonyl; PEG (polyethylene glycol) 2 3-oxo-2, 7, 10-trioxa-4-azatridec-13-oic acid, AEEA is 8-amino-3, 6-dioxaoctanoic acid; TFA is trifluoroacetic acid; DODT is 2,2' - (1, 2-ethanediyl dioxy) bis ethanethiol; ACN is acetonitrile.
Drawings
FIG. 1 is a graph of time-blood glucose results of the OGTT assay of example 2 after 0.5h of mice dosing;
FIG. 2 is an area under the blood glucose curve (AUC) of FIG. 1;
FIG. 3 is a graph of time-blood glucose results of the OGTT assay for mice administered for 1h in example 2;
FIG. 4 is an area under the blood glucose curve (AUC) of FIG. 3;
FIG. 5 is a graph of time-blood glucose results of the OGTT experiment 24 hours after administration of mice in example 3;
FIG. 6 is an area under the blood glucose curve (AUC) of FIG. 5;
FIG. 7 is a graph of time-blood glucose results of the OGTT experiment 48 hours after administration of mice in example 3.
FIG. 8 is an area under the blood glucose curve (AUC) of FIG. 7;
fig. 9 is a graph of time-blood glucose results of OGTT experiments after 72h dosing of mice in example 3.
FIG. 10 is an area under the blood glucose curve (AUC) of FIG. 9;
FIG. 11 is a graph of time-blood glucose results of the OGTT experiment for mice in example 3 96 hours post-dose.
FIG. 12 is an area under the blood glucose curve (AUC) of FIG. 11;
FIG. 13 is a graph of time-blood glucose results of the OGTT experiment for mice administered for 120h in example 3.
FIG. 14 is an area under the blood glucose curve (AUC) of FIG. 13;
fig. 15 is a graph of time-blood glucose results of OGTT experiments after 144h of mice in example 3.
FIG. 16 is an area under the blood glucose curve (AUC) of FIG. 15;
fig. 17 is a graph of time-blood glucose results of OGTT experiments for 168h post-administration in mice of example 3.
FIG. 18 is an area under the blood glucose curve (AUC) of FIG. 17;
FIG. 19 is a statistical chart of the weight monitoring data of mice in example 4;
FIG. 20 is a graph showing the statistics of fasting blood glucose monitoring in mice of example 4;
FIG. 21 is a graph of time-blood glucose results of the OGTT experiment 24h after administration of mice in example 5;
fig. 22 is an area under the blood glucose curve (AUC) of fig. 21.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Materials and methods:
Boc-His (Trt) -OH, fmoc-Aib-OH was purchased from Shanghai Jil, mono-tert-butyl eicosadioate. The remaining amino acids were purchased from Chengdu Zheng Yuan, and the condensing agent was purchased from Suzhou-Haihai. All other reagents were analytically pure and solvents were purchased from Shanghai Taitan, inc., unless otherwise specified. The centrifuge was purchased from Lu Xiangyi. 5.0cm inverted C 18 A column (46 mm X250 mm) was prepared for purification of the polypeptide. The high performance liquid chromatograph is the product of the Siemens company. Mass spectrometry was performed using a Waters mass spectrometer。
EXAMPLE 1 Synthesis of polypeptide Compounds
1. Synthesis of Compound 31
Amino acid sequence of compound 31:
Tyr-Iva-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Ile-Ala-Gln-Lys(Gl y-Gly-Ser-Gly-Ser-Gly-Ser-Gly-γGlu-CO(CH 2 ) 18 CO 2 H)-Ala-Phe-Val-Gln-Trp-Leu-Ile-Ala-Gl y-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2
the abbreviation is: Y-Iva-EGTFTSDYSI-Aib-LDKIAQK (GGSGSG-gamma Glu-CO (CH) 2 ) 18 CO 2 H)AFV QWLIAGGPSSGAPPPS-NH 2
The method comprises the following steps:
step 1, synthesizing main peptide resin corresponding to main peptide chain
Manual synthesis according to Fmoc/t-Bu strategy, scale of synthesis: 0.5mmol, the following main peptide resin was synthesized:
Boc-Tyr(tBu)-Iva-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys-Ile-Ala-Gln(Trt)-Lys(Alloc)-Ala-Phe-Val-Gln(Trt)-Trp(Bo c)-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Rink Amide AM Resin。
(1): 0.89 g of Rink Amide AM Resin Resin resin (loading 0.56mmol/g, sian Lan Xiao) was weighed into a reaction column, swollen for 30min in 15ml of DMF and Fmoc-Ser (tBu) -OH was weighed: 1.587g (6 eq), HOBt:0.672g (7.2 eq), DMAP:0.06g (0.72 eq) for use. The DMF was removed and the resin was washed thoroughly with DMF 2 times and the above weighed material was added to the reaction column. Appropriate amount of DMF was added, and the mixture was stirred well with nitrogen, and 0.83mL (7.8 eq) of DIC was added. The reaction is carried out for 2 hours, and the reaction is finished. The reaction solution was removed, washed 3 times with DMF and blocked by the addition of acetic anhydride/pyridine (7:6, v/v) for 4h. The blocking solution was removed and washed 6 times with DMF to give Fmoc-Ser (tBu) -Rink Amide AM Resin.
(2): fmoc-Ser (tBu) -Rink Amide AM Resin is used as a carrier, HOBt and DIC are used as coupling agents, DMF is used as a solvent, 20% of Piperidine/DMF solution is used for removing Fmoc groups (5 min and 7min twice), and ninhydrin is used for monitoring the coupling effect in the coupling process. Performing manual feeding, and sequentially performing condensation reaction from the C end to the N end to connect Fmoc-Pro-OH, fmoc-Pro-OH, fmoc-Pro-OH, fmoc-Ala-OH, fmoc-Gly-OH, fmoc-Ser (tBu) -OH, fmoc-Pro-OH, fmoc-Gly-OH, fmoc-Gly-OH, fmoc-Ala-OH, fmoc-Ile-OH, fmoc-Leu-OH, fmoc-Trp (Boc) -OH, fmoc-Gln (Trt) -OH, fmoc-Val-OH, fmoc-Phe-OH, fmoc-Ala-OH, fmoc-Lys (Alloc) -OH, fmoc-Gln (Trt) -OH, fmoc-Ala-OH, fmoc-Ile-OH, fmoc-Lys (Boc) -OH, fmoc-Asp (OtBu) -OH, fmoc-Leu-OH, fmoc-Aib-OH, fmoc-Ile-OH, fmoc-Ser (tBu) -OH, fmoc-Se r (tBu) -OH, fmoc-Tyr (tBu) -OH, fmoc-Asp (OtBu) -OH, fmoc-Ser (tBu) -OH, fmoc-Thr (tBu) -OH, fmoc-Phe-OH, fmoc-Thr (tBu) -OH, fmoc-Gly-OH, fmoc-Glu (tBu) -OH, fmoc-Iva-OH, boc-Tyr (tBu) -OH. The above amino acid addition corresponds to a synthesis scale of 5eq, resulting in Boc-Tyr (tBu) -Iva-Glu (tBu) -Gly-Thr (tBu) -Phe-Thr (tBu) -Ser (tBu) -Asp (OtBu) -Tyr (tBu) -Ser (tBu) -Ile-Ai-b-Leu-Asp (OtBu) -Lys-Ile-Ala-Gln (Trt) -Lys (Alloc) -Ala-Phe-Val-Gln (Trt) -Trp (Boc) -Leu-Ile-Ala-Gly-Pro-Ser (tBu) -Gly-Ala-Pro-Pro-Ser (tBu) -Rink Amide AM Resin.
There are several points to be described:
1) Fmoc-Ser (tBu) -Rink Amide AM Resin is synthesized, because Rink Amide AM Resin is low in substitution rate, the feeding amount of Fmoc-Ser (tBu) -OH is large, otherwise, the substitution rate is low, and materials are wasted. Blocking with acetic anhydride/pyridine prevents the appearance of defective peptides.
2) In each subsequent condensation reaction, fmoc protected amino acid, HOBt and DIC were fed in 5 times, and the reaction time was 2 hours.
3) The coupling process uses ninhydrin to monitor the coupling effect, if the detection is negative, the reaction is complete, and if the detection is positive, the reaction is required to be repeated once again. Fmoc protected amino acid, HOBt, DIC were fed in 2 times, and the reaction time was 1 hour. If positive, blocking was performed for 2h with the addition of acetic anhydride/pyridine (7:6, v/v).
(3): removal of allyloxycarbonyl (Alloc)
DCM was added to the resin, morpholine 0.5mL (12 eq) was added, and 0.173g Pd (PPh) 3 ) 4 (0.3 eq) was added to the reaction column and reacted for 1h. At the end of the reaction, the reaction solution was withdrawn, washed 3 times with DMF and 6 times with DCM. Obtaining the main peptide chain peptide resin: boc-Tyr (tBu) -Iva-Glu (tBu) -Gly-Thr (tBu) -Phe-Thr (tBu) -Ser (tBu) -Asp (OtBu) -Ty r (tBu) -Ser (tBu) -Ile-Aib-Leu-Asp (OtBu) -Lys-Ile-Ala-Gln (Trt) -Lys-Ala-Phe-Val-Gln (Trt) -Trp (Boc) -Leu-Ile-Ala-Gly-Gly-Pro-Ser (tBu) -Ser (tBu) -Gly-Ala-Pro-Pro-Pro-Ser (tBu) -Rink Amide AM Resin.
Step 2, coupling a side arm structure:
Fmoc-Gly-OH coupling: fmoc-Gly-OH, HOBt and a proper amount of DMF are added into the main peptide resin product, the mixture is stirred uniformly by nitrogen, DIC is added, the mixture is stirred by nitrogen for 2 hours, the coupling effect is detected by ninhydrin, and the mixture is colorless and transparent, and the reaction is finished. The reaction solution was removed, washed 3 times with N, N-Dimethylformamide (DMF), fmoc groups were removed with a 20% solution of Piperidine/DMF (5 min+7min twice), after Fmoc removal, washed 6 times with DMF, and the sample was taken and tested positive for ninhydrin and the subsequent coupling step was entered.
The above operations were repeated to couple Fmoc-Gly-OH, fmoc-Ser (tBu) -OH, fmoc-Gly-OH, fmoc-Ser (tBu) -OH, fmoc-Gly-OH, fmoc-Ser (tBu) -OH, fmoc-Gly-OH, fmoc-Glu-OtBu, and eicosanedioic acid mono-tert-butyl ester in sequence. Obtaining Boc-Tyr (tBu) -Iva-Glu (tBu) -Gly-Thr (tBu) -Phe-Thr (tBu) -Ser (tBu) -As p (OtBu) -Tyr (tBu) -Ser (tBu) -Ile-Aib-Leu-Asp (OtBu) -Lys-Ile-Ala-Gln (Trt) -Lys (Gly-Gly-Ser (tBu) -Gly-Ser (tBu) -Gly-Ser (tBu) -Gly-Glu-OtBu-CO (CH) 2 ) 18 CO 2 -tBu) -Ala-Phe-Val-Gln (Trt) -Trp (Boc) -Leu-Ile-Ala-Gly-Gly-Pro-Ser (tBu) -Ser (tBu) -Gly-Ala-Pro-Pro-Pro-Ser (tBu) -Rink Amide AM Resin. 3 times with DMF, 3 times with DCM, 2 times with MeOH shrinkage, and vacuum drying to give 3.2g of dried polypeptide resin.
Step 3, removing the full protection of the polypeptide
Lysate: TFA, DODT, m-cresol, H 2 The volume ratio of O is 92.5:2.5:2.5:2.5, and freezing in a refrigerator for 2 hours.
To the dried polypeptide resin Boc-Tyr (tBu) -Iva-Glu (tBu) -Gly-Thr (tBu) -Phe-Thr (tBu) -Ser (tBu) -Asp (OtBu) -Tyr (tBu) -Ser (tBu) -Il, 10mL of lysate per g of polypeptide resine-Aib-Leu-Asp(OtBu)-Lys-Ile-Ala-Gln(Trt)-Lys(Gly-Gly-Ser(tBu)-Gly-Ser(tBu)-Gly-Ser(tBu)-Gly-Glu-OtBu-CO(CH 2 ) 18 CO 2 The lysate was added to (tBu) -Ala-Phe-Val-Gln (Trt) -Trp (Boc) -Leu-Ile-Ala-Gly-Gly-Pro-Ser (tBu) -Ser (tBu) -Gly-Ala-Pro-Pro-Pro-Ser (tBu) -Rink Amide AM Resin, and the reaction was continued for 3 hours at room temperature. The filtrate was collected by filtration, the resin was washed 3 times with a small amount of lysate, the filtrates were combined, concentrated under reduced pressure to about 1/4 of the original volume, slowly poured into ice methyl tert-butyl ether with stirring, and the residue in the bottle was washed with a small amount of lysate together into methyl tert-butyl ether. Standing for more than 2 hours until the precipitation is complete. Removing supernatant, centrifuging the precipitate, washing 3 times with methyl tertiary butyl ether, centrifuging, and drying the solid with nitrogen. Obtaining crude compound Tyr-Iva-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Ile-Ala-Gln-Lys (Gly-Gly-Ser-Gly-Ser-Gly-Ser-Gly-gamma Glu-CO (CH) 2 ) 18 CO 2 H)-Ala-Phe-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 . The crude product weighed 1.48g.
Step 4. Refining and purifying the crude compound
Dissolving the crude compound obtained in step 3 in ACN: h 2 O=1: 3 (v/v) in solution by 5.0cm of reversed phase C 18 Is subjected to preparative HPLC purification on a packed 46mm x 250mm column. With 39% ACN/H 2 O (0.1% trifluoroacetic acid) was used as an initial step, the column was eluted at a gradient (0.33%/min increasing ACN ratio) at a flow rate of 80mL/min for 60 minutes, and fractions containing the polypeptide were collected to give a sample with an HPLC purity of greater than 90%. HPLC purification was repeated once with 29% ACN/H 2 O (containing 0.1% acetic acid) is used as an initial step, gradient (0.33%/min ratio of increasing ACN) is adopted, the flow rate is 80mL/min, the column is eluted for 60 min, the polypeptide-containing component is collected, and freeze drying is carried out, so that 440mg of refined peptide is obtained, the purity is more than 98.96%, and the total yield is 17%.
Step 5. Product confirmation
Identification of isolated product polypeptide by LC-MS using 5% ACN/H 2 O (0.1% formic acid) as an initial starting point, increasing the ACN ratio at a gradient (6%/min),the flow rate was 0.4mL/min, and the elution was performed for 15 minutes to determine the target compound 31, [ M+H ]] + Calculated as 5083.73, [ M+3H ]] 3+ The actual measurement value was 1695.20.
2. Synthesis of Compound 35
Since compound 35 differs from compound 31 only in that X13 in the sequence of the main peptide chain is different, X13 in 35 is Iva, the two synthetic steps differ in that step 1 synthesizes the following main peptide resin different from compound 31:
Boc-Tyr (tBu) -Iva-Glu (tBu) -Gly-Thr (tBu) -Phe-Thr (tBu) -Ser (tBu) -Asp (OtBu) -Tyr (tBu) -Ser (tBu) -Ile-Iva-Leu-Asp (OtBu) -Lys-Ile-Ala-Gln (Trt) -Lys (Alloc) -Ala-Phe-Val-Gln (Trt) -Trp (Boc) -Leu-Ile-Ala-Gly-Gly-Pro-Ser (tBu) -Ser (tBu) -Gly-Ala-Pro-Pro (tBu) -Rink Amide AM Resin on a scale: 0.5mmol.
Subsequent side chain coupling and cleavage of compound 35 is the same as compound 31.
The purification and product confirmation method of compound 35 was the same as that of compound 31 to obtain 332mg of refined peptide with a purity of more than 98.46% and a total yield of 13%. Identification of the isolated product by LC-MS, determination of Compound 35, [ M+H ]] + Calculated as 5097.76, [ M+3H ]] 3+ The actual measurement value was 1699.90.
3. Synthesis of Compound 38
Since compound 38 differs from compound 31 in that X2, X13, X27, X28 in the sequence of the main peptide chain are different, X2 in compound 38 is Aib, X13 is Iva, X27 is Leu, X28 is Asp, the two synthetic steps differ in that step 1 synthesizes a main peptide resin:
manual synthesis according to Fmoc/t-Bu strategy, scale of synthesis: 0.5mmol, the following main peptide resin was synthesized: boc-Tyr (tBu) -Aib-Glu (tBu) -Gly-Thr (tBu) -Phe-Thr (tBu) -Ser (tBu) -Asp (OtBu) -Tyr (tBu) -Ser (tBu) -Ile-Iva-Leu-Asp (OtBu) -Lys-Ile-Ala-Gln (Trt) -Lys (Alloc) -Ala-Phe-Val-Gln (Trt) -Trp (Boc) -Leu-Leu-Asp (OtBu) -Gly-Gly-Pro-Ser (tBu) -Ser (tBu) -Gly-Ala-Pro-Pro-Ser (tBu) -Rink Amide AM Re sin.
Subsequent side chain coupling and cleavage of compound 38 is identical to compound 31.
The purification of compound 38 and the confirmation of the product were carried out in the same manner as in compound 31 to obtain 385mg of refined peptide with a purity of more than 98.35% and a total yield of 15%. Identification of the isolated product by LC-MS, identified as Compound 38, [ M+H ]] + Calculated as 5128.69, [ M+3H ]] 3+ The actual measurement value was 1709.50.
Based on the above synthetic steps, the purification and product confirmation method adjusts the coupling sequence of the resin in the synthetic step 1 or step 2 of the compound according to the distinguishing sites in the peptide chain of the compound 1-60, finally synthesizes the corresponding target product, identifies the separated product by liquid chromatography-mass spectrometry, confirms the m/z value (measured value in table 1) of the ion peak of the protonated molecule, compares the measured value with the theoretical value of molecular weight, and confirms that the synthesized and purified product is the target product. The theoretical molecular weight, liquid quality, sequence and molecular formula of compounds 1-60 are shown in Table 1, respectively.
Table 1 amino acid sequence and LC-MS identification results of long-acting polypeptide compounds
/>
/>
/>
/>
/>
/>
Example 2 Effect of Compounds 1-27 and Soxhaust Ma Lutai (Semaglutide) on glucose tolerance in C57BL/6J mice
In vivo efficacy studies were performed on compounds 1-27, and the effect and maintenance time of glucose tolerance of compounds 1-27 and semaglutin at the same dose on normal mice were studied by Oral Glucose Tolerance Test (OGTT).
The experimental method comprises the following steps: the test used 8 week old C57BL/6J male mice (from Guangdong Jiajing Biotechnology Co., ltd.) and 7 animals/group, all compounds and Semaglutide (injection, from Guangzhou Tung Toku Tochu pharmaceutical Co., ltd.) were dosed at 50. Mu.g/kg. First, the weight and random blood glucose of the mice were measured prior to the test and regrouped according to weight and random blood glucose, ensuring that the average weight and random blood glucose average for each group is similar. The medicines are prepared on the same day of administration, the corresponding medicines are injected subcutaneously according to groups, and OGTT tests are respectively carried out after 0.5h and 1h of administration (parallel experiments, one group of mice carries out the 0.5h OGTT test, and the other group of mice carries out the 1h OGTT test). Glucose was administered by gavage at a dose of 2g/kg and blood glucose levels were measured at 6 time points for 0, 15, 30, 60, 90 and 120min after gavage by tail vein blood sampling. Data were processed using software GraphPadPrism, time-blood glucose plots were plotted and the area under the blood glucose curve AUC was calculated. One-way ANOVA analysis was performed with the non-dosed PBS control group to calculate the significant differences. The test results are shown in fig. 1-4, wherein, p <0.05; * Represents p <0.01; * Represents p <0.001; * P <0.0001.
Analysis of results: as can be seen from fig. 1-2, at 0.5h after administration, the glucose tolerance was significantly improved in all administration groups compared with PBS at each time point of blood sampling, and the hypoglycemic effect was significantly (i.e., p.ltoreq.0.0001), and there was no significant difference between the groups.
As can be seen from fig. 3-4, compounds 4-14, 16-21 and 23-27 still improved glucose tolerance compared to PBS after 1h administration, with significant hypoglycemic effect (i.e., p.ltoreq.0.0001), but the AUC values increased slightly with respect to 0.5h post administration. After 1h of administration, compounds 1-3, 15 and 22 had no statistically significant differences compared to PBS, losing the hypoglycemic effect.
Example 3: effect of Compounds 28-61 and Semaglutide on glucose tolerance in C57BL/6J mice
In vivo efficacy study is carried out on the compound 28-60, and the compound 61 is taken as a control group, and the influence and the maintenance time of the compound 28-61 and Semaglutide on the glucose tolerance of normal mice at the same dosage are studied through an oral glucose tolerance experiment (OGTT) experiment.
The experimental method comprises the following steps: the test used 8 week old C57BL/6J male mice (from Guangdong Jiajing Biotechnology Co., ltd.) and 7 animals/group, all compounds and Semaglutide (injection, from Guangzhou Tung Toku Tochu pharmaceutical Co., ltd.) were administered at 80. Mu.g/kg. First, the weight and random blood glucose of the mice were measured prior to the test and regrouped according to weight and random blood glucose, ensuring that the average weight and random blood glucose average for each group is similar. The medicines are prepared on the same day of administration, and the corresponding medicines are injected subcutaneously according to groups. The glucose OGTT test was performed 24h, 48h, 72h, 96h, 120h, 144h, 168h after administration, glucose was administered by gavage at a dose of 2g/kg, and blood glucose values at 6 time points total after gavage were measured by tail vein blood sampling. Data were processed using software GraphPadPrism, time-blood glucose plots were plotted and the area under the blood glucose curve AUC was calculated. One-way ANOVA analysis was performed with the non-dosed PBS control group to calculate the significant differences. The test results are shown in fig. 5-18, wherein p <0.05; * Represents p <0.01; * Represents p <0.001; * P <0.0001.
Analysis of results:
(1) 24h of results. As can be seen from FIGS. 5-6, all compounds significantly improved glucose tolerance and reduced glycemic effect compared to the PBS control. Among them, the compounds 31-36, 38-39, 41-52, 55-60 and Semaglutide have the most remarkable hypoglycemic effect.
(2) 48h of results. As can be seen from fig. 7-8, all compounds significantly improved glucose tolerance and reduced blood glucose levels compared to the PBS control. Wherein, compounds 31, 33, 35, 38-39, 41-52 and 55-60 are most effective, approaching 24 h; the efficacy of the compounds 53, 54 is the next time; and then compounds 37, 40, 61; finally compounds 29, 30; the effects of compounds 28, 32, 34, 36 and Semaglutide are equivalent, and the efficacy is reduced compared with 24 hours.
(3) 72h of result. As can be seen from fig. 9-10, compounds 31, 33, 35, 38, and compounds 39-60 still have better potency, slightly weaker than 48h potency; compounds 29, 30, 61 were less potent, and lost efficacy, as compared to PBS control compounds 28, 32, 34, 36 and semaglutine.
(4) 96h results. As can be seen from fig. 11-12, compounds 38, 39, 43, 44, 55, 58, 59, 60 still have efficacy, but less than 72 hours; compounds 31, 33, 35, 37, 40, 49, 50 were the next time effective; followed by compounds 51, 52, 53, 54; finally, compounds 29, 30; there was no significant difference between compounds 28, 32, 34, 36, 41, 42, 45-48, 53, 56-57, 61 and semaglutinide compared to the PBS control group, and efficacy was lost.
(5) 120h of results. As can be seen from fig. 13-14, wherein compounds 38, 39, 43, 44, 55, 58, 59, 60 still have efficacy, efficacy is weaker than 96 hours; compounds 31, 33, 35, 37, 40, 49-54 were the next time effective; then compounds 29 and 30 have weaker drug effects; there were no significant differences, no efficacy, and consistent efficacy-free results for 72h, 96h compared to PBS control compounds 28, 32, 34, 36, 41, 42, 45-48, 56-57, 61 and semaglutine.
(6) 144h results. As can be seen from fig. 15-16, compounds 38, 39, 43, 44, 55, 58 still have efficacy, which is weaker than 120h; compounds 49, 50, 51, 52, 53, 54, 59 were less potent, followed by compounds 31, 33, 35, 37, 40; there were no significant differences between compounds 28, 29, 30, 32, 34, 36, 41, 42, 45-48, 56-57, 60, 61 and semaglutine compared to the PBS control, and efficacy was lost.
(7) 168h of results. As can be seen from fig. 17-18, compounds 38, 39, 43, 44, 55, 58 still have weak potency compared to PBS control; 49. 50, 51, 52, 53, 54, 59; the other compounds lose their efficacy.
Conclusion: analysis of the above results revealed that Semaglutide had good effects with each compound, although improving glucose tolerance. However, the duration of efficacy of each compound varies in terms of the duration of efficacy, i.e., in terms of long-acting hypoglycemic. Among them, the compounds 38, 39, 43, 44, 55, 58, 49, 50, 51, 52, 53, 54, 59 have remarkable advantages in both efficacy and duration of efficacy (long-lasting), and are far superior to Semaglutide.
Example 4: therapeutic effects of Compounds 31, 33, 35, 38, 39, 43, 44, 49, 58, 60 and Semaglutide on BKS-db diabetic mice
Based on the OGTT experimental results, we further studied the efficacy of compounds 31, 33, 35, 38, 39, 43, 44, 49, 58, 60 on the BKS-db diabetic mouse model, and examined the effect of the compounds on body weight and blood glucose.
The experimental method comprises the following steps: the test used BKS-db diabetic mice (available from Guangdong pharmaceutical biotechnology Co., ltd.) with Lepr KO/KO genotype at 8 weeks. Blood glucose and body weight were measured and randomly grouped according to body weight and blood glucose, with 6 each, divided into each compound group, positive control group (Semaglutide) and model control group (PBS). Each group of mice was subcutaneously injected with compound 31, 33, 35, 38, 39, 43, 44, 49, 58, 60, semaglutinide (injection available from the pharmaceutical company of tunghuahui, guangzhou) at a dose of 120 μg/kg once a day, and the control group was injected with an equal volume of physiological saline. The test period was 4 weeks. After each dose, 6h fasted every other day, mice were tested for blood glucose and body weight and data were recorded, data were processed using the software GraphPadPrism, experimental results are shown in fig. 19-20, where x represents p <0.05; * Represents p <0.01; * Represents p <0.001; * P <0.0001.
Analysis of results:
(1) Statistical analysis of the body weight monitoring data of mice is shown in fig. 19. The results show that compounds 31, 33, 35, 38, 39, 43, 44, 49, 58, 60 are all effective in reducing body weight in mice compared to model control (PBS), and the body weight-reducing effect is superior to semaglutinide.
(2) Statistical analysis of fasting blood glucose monitoring data for mice is shown in fig. 20. The results show that compounds 31, 33, 35, 38, 39, 43, 44, 49, 58, 60 and semaglutine all significantly reduced fasting blood glucose levels in BKS-db diabetic mice compared to model control (PBS), indicating that these compounds all have significant hypoglycemic effects. Blood glucose had fallen to normal levels by week 1, and thereafter the blood glucose of groups 31, 33, 35, 38, 39, 43, 44, 49, 58, 60 was relatively stable and superior to Semaglutide in effect.
Example 5: lixisenatide and pharmacodynamic verification test of modified peptide thereof
The synthesized compound 62 is Lixisenatide (Lixisenatide) which is a GLP-1 receptor agonist polypeptide medicament on the market, and the compound 63 is a side chain Gly-Gly-Ser-Gly-Ser-Gly-Ser-Gly-gamma-Glu-CO (CH) related to the invention 2 ) 18 CO 2 Compound 64 is side chain Gly-Gly-Ser-Gly-Ser-Gly-Ser-Gly-gamma-Glu-CO (CH) related by the invention 2 ) 18 CO 2 H modifies Lys at position 26 of lixisenatide. The pharmacological effects of compound 62, compound 63, compound 64 on oral glucose tolerance (OGTT) of mice were studied.
The experimental method comprises the following steps: male C57BL/6J mice (purchased from Guangdong Jiajing reaching biotechnology Co., ltd.) of about 8 weeks old were raised for one week to adapt to the environment, and were randomly grouped according to blood glucose, 8 animals per group. Each polypeptide compound was administered subcutaneously at a dose of 80ug/kg, and the control group was given the same volume of PBS. The day of administration was fasted for 16h at night, glucose was administered by gavage at a dose of 2g/kg 24h after administration, and blood glucose values were detected at t=0 min, t=15 min, t=30 min, t=60 min, t=90 min, and t=120 min. Data were processed using software GraphPadPrism, time-blood glucose plots were plotted and the area under the blood glucose curve AUC was calculated. One-way ANOVA analysis was performed with the non-dosed PBS control group to calculate the significant differences.
Analysis of results: from the OGTT result data statistics (fig. 21-22) it is known that: compound 62 (lixiviapeptide) significantly reduced AUC compared to vehicle (PBS) 24h after dosing, demonstrating that lixiviapeptide has significant glucose tolerance, which is effective in lowering blood glucose; the compound 63 and the compound 64 after the side chain modification of the lixisenatide have no obvious influence on AUC, which indicates that the glucose tolerance cannot be improved and the blood sugar cannot be effectively reduced by modifying the peptide only through the side chain modification.
Conclusion: the side chain of the present application is added to lixiviated peptide, but the hypoglycemic effect is not prolonged, but the original peptide loses the hypoglycemic effect. Thus, it can be stated that: the side chain attachment of the polypeptide compounds according to the invention is not generally applicable to other peptides, but is independently inventive.
Example 6: pharmacokinetic study of Compound 33, compound 35, compound 38, compound 39, compound 43, compound 44, compound 58, compound 61 in SD rats
SD rats (SPF grade, source S Bei Fu (Beijing) biotechnology Co., ltd.) were fed with SCXK 2019-0010, weight: 180-200 g, age: 6-8 weeks for one week to adapt to the environment, and the animals with failed period were examined for general status of the animals, and the feeding environment control system was a WINCC7.3 EMS series machine room environment monitoring system, and the feed was maintained using SPF-sized rats. The 20 qualified SD rats were randomly grouped according to body weight, 4 animals (male and female halves) in 5 groups (animals were grouped and statistically analyzed using software Stata 15).
In this example, the compound was administered subcutaneously to the skin of the nape of the neck in a single dose of 0.15mg/kg or 0.2mg/kg at a dose volume of 2mL/kg and at a concentration of 0.075mg/mL or 0.1mg/mL in PBS.
Rats in the single subcutaneous administration group were blood-sampled via the jugular vein before (0 h) and after (0.5 h, 1h, 2h, 4h, 6h, 8h, 24h, 48h, 72h, 96h, 120h, 144h, 168h, 192h, with an amount of about 0.2mL whole blood collected at each time point at EDTA-K 2 In an anticoagulant tube, the tube is centrifuged for 10m at 4 ℃ and 1800g centrifugal force within 1hin, taking supernatant, and transferring the separated plasma to a refrigerator at-80 ℃ for preservation. And (3) respectively establishing a concentration analysis method of the compound in the plasma of the SD rat by using UPLC-MS/MS, and determining the drug concentration of the compound in the plasma. The pharmacokinetic parameters were calculated by using WinNonlin 8.1 software for data processing, and the experimental results are shown in table 2.
As can be seen from the experimental results, compound 33, compound 35, compound 38, compound 39, compound 43, compound 44 and compound 58 were absorbed more slowly in rats and reached the peak time T after single subcutaneous administration of compound 33, compound 35, compound 38 and compound 58 max All are about 24 hours, obviously higher than that of compound 61 for 8 hours, half-life t 1/2 Average 12.2h, 17.8h, 18.8h, 22.3h, 25.5h, 21.7h, 20.4h, respectively, are significantly higher than 10.8h of compound 61, and the half-life of compound 39 can reach over 22 h. From this, it can be confirmed that the long-acting polypeptide compound of the present invention has a longer half-life.
TABLE 2 in vivo pharmacokinetic experiment results for SD rats and corresponding dosing amounts for the compounds
Compounds of formula (I) | T 1/2 (h) | T max (h) | Dosage mg/kg |
33 | 12.2 | 24 | 0.2 |
35 | 17.8 | 24 | 0.2 |
38 | 21.8 | 24 | 0.2 |
39 | 22.3 | 24 | 0.2 |
43 | 20..5 | 24 | 0.2 |
44 | 21.7 | 24 | 0.2 |
58 | 20.4 | 24 | 0.2 |
61 | 10.8 | 8 | 0.15 |
The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily appreciate variations or alternatives within the scope of the present invention. Therefore, the protection scope of the invention is subject to the protection scope of the claims.
Claims (13)
1. A novel long-acting polypeptide compound, characterized in that the amino acid sequence of the long-acting polypeptide compound is as follows:
X1-X2-X3-GTFTSDYSI-X13-LDKIAQ-X20-AFVQWL-X27-X28-GGPSSG-X35-PPPS-R 1 ;
wherein X3 is selected from E, Q or N; x27 is selected from L or I; x28 is selected from A or D; x35 is selected from A or Aib; x20 is K, K (G) x (SG) Z -γGlu-CO(CH 2 ) a CO 2 H)、K((PEG 2 ) b -γGlu-CO(CH 2 ) c CO 2 H) Or K ((AEEA) d -γGlu-CO(CH 2 ) e CO 2 H) Wherein x is an integer of 0 to 5, z is an integer of 1 to 5, and a is an integer of 12 to 20; b is an integer of 1-8, c is an integer of 12-20; d is an integer of 1-8, e is an integer of 12-20; r is R 1 Selected from OH or NH 2 ;
When X2 is selected from Aib, iva or Cba: x1 is selected from H or Y; x13 is selected from Aib, iva or Cba;
when X2 is D-Ser: x1 is H; x13 is selected from Aib, iva or Cba.
2. The long acting polypeptide compound of claim 1, wherein when X20 is selected from K (G x (SG) Z -γGlu-CO(CH 2 ) a CO 2 H)、K((PEG 2 ) b -γGlu-CO(CH 2 ) c CO 2 H) Or K ((AEEA) d -γGlu-CO(CH 2 ) e CO 2 H) When G x (SG) Z -γGlu-CO(CH 2 ) a CO 2 H、(PEG 2 ) b -γGlu-CO(CH 2 ) c CO 2 H or (AEEA) d -γGlu-CO(CH 2 ) e CO 2 H is linked to the main peptide chain of the long-acting polypeptide compound by amide bond formation with the side chain amino group of K.
3. The long-acting polypeptide of claim 1A compound wherein X20 is K (G x (SG) Z -γGlu-CO(CH 2 ) a CO 2 H) Where x is 2, z is 2 or 3, and a is 16 or 18.
4. The long acting polypeptide compound of claim 1, wherein X35 is a.
5. The long acting polypeptide compound of claim 1, wherein X1 is Y, X2 is selected from Aib, iva or Cba, X3 is E, and X13 is selected from Aib, iva or Cba.
6. The long-acting polypeptide compound of claim 5,
x2 is Iva, X13 is Aib or Iva;
alternatively, X2 is Aib and X13 is Iva.
7. The long acting polypeptide compound of claim 1, wherein X1 is H, X2 is selected from Aib, iva or Cba, and X3 is selected from E or Q; x13 is selected from Aib, iva or Cba.
8. The long acting polypeptide compound of claim 7, wherein X2 is Aib or Iva and X13 is Iva.
9. The long-acting polypeptide compound of claim 1, wherein amino acid D at position 9 and amino acid K at position 16 are linked by an amide bond.
10. The long-acting polypeptide compound of claim 1, wherein the long-acting polypeptide compound is selected from any one of the following compounds:
Compound 1:
Y-Aib-QGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSG-Aib-PPPS-OH;
compound 2:
Y-Aib-QGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH;
compound 3:
Y-Aib-EGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH;
compound 4:
Y-Iva-EGTFTSDYSI-Aib-LDKIAQKAFVQWLIAGGPSSGAPPPS-OH;
compound 5:
Y-Aib-EGTFTSDYSI-Iva-LDKIAQKAFVQWLIAGGPSSGAPPPS-OH;
compound 6:
Y-Iva-EGTFTSDYSI-Iva-LDKIAQKAFVQWLIAGGPSSGAPPPS-OH;
compound 7:
Y-Iva-EGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH;
compound 8:
Y-Aib-EGTFTSDYSI-Iva-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH;
compound 9:
Y-Iva-EGTFTSDYSI-Iva-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 10:
Y-Iva-QGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 11:
Y-Cba-EGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 12:
Y-Cba-EGTFTSDYSI-Iva-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 13:
Y-Aib-EGTFTSDYSI-Cba-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 14:
Y-Iva-EGTFTSDYSI-Cba-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 15:
H-Aib-EGTFTSDYSI-Aib-LDKIAQKAFVQWLLAGGPSSGAPPPS-OH; compound 16:
H-Iva-QGTFTSDYSI-Aib-LDKIAQKAFVQWLLAGGPSSGAPPPS-OH; compound 17:
H-Iva-EGTFTSDYSI-Iva-LDKIAQKAFVQWLLAGGPSSGAPPPS-OH; compound 18:
H-Iva-QGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 19:
H-Iva-EGTFTSDYSI-Iva-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH; compound 20:
H-Cba-QGTFTSDYSI-Aib-LDKIAQKAFVQWLIAGGPSSGAPPPS-OH; compound 21:
H-Cba-QGTFTSDYSI-Iva-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH;
compound 22:
H-(D-Ser)-QGTFTSDYSI-Aib-LDKIAQKAFVQWLLDGGPSSGAPPPS-OH;
compound 23:
Y-Iva-EGTFTS(D)YSI-Iva-LD(K)IAQKAFVQWLIAGGPSSGAPPPS-OH, wherein amino acid D at position 9 is linked to amino acid K at position 16 by an amide bond;
Compound 24:
Y-Aib-EGTFTS(D)YSI-Iva-LD(K)IAQKAFVQWLLDGGPSSGAPPPS-OH, wherein amino acid D at position 9 is linked to amino acid K at position 16 by an amide bond;
compound 25:
Y-Iva-EGTFTS(D)YSI-Iva-LD(K)IAQKAFVQWLLDGGPSSGAPPPS-OH, wherein amino acid D at position 9 is linked to amino acid K at position 16 by an amide bond;
compound 26:
H-Aib-QGTFTS(D)YSI-Aib-LD(K)IAQKAFVQWLLDGGPSSGAPPPS-OH, wherein amino acid D at position 9 is linked to amino acid K at position 16 by an amide bond;
compound 27:
H-Iva-EGTFTS(D)YSI-Aib-LD(K)IAQKAFVQWLLDGGPSSGAPPPS-OH, wherein amino acid D at position 9 is linked to amino acid K at position 16 by an amide bond;
compound 28:
Y-Aib-QGTFTSDYSI-Aib-LDKIAQK(GGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLDGG PSSG-Aib-PPPS-NH 2 ;
compound 29:
Y-Aib-QGTFTSDYSI-Aib-LDKIAQK(GGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLDGG PSSGAPPPS-NH 2 ;
compound 30:
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK(GGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLDGG PSSGAPPPS-NH 2 ;
compound 31:
Y-Iva-EGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIA GGPSSGAPPPS-NH 2 ;
compound 32:
Y-Iva-EGTFTSDYSI-Aib-LDKIAQK(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIAG GPSSGAPPPS-NH 2 ;
compound 33:
Y-Aib-EGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIA GGPSSGAPPPS-NH 2 ;
compound 34:
Y-Aib-EGTFTSDYSI-Iva-LDKIAQK(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIAG GPSSGAPPPS-NH 2 ;
compound 35:
Y-Iva-EGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIA GGPSSGAPPPS-NH 2 ;
compound 36:
Y-Iva-EGTFTSDYSI-Iva-LDKIAQK(AEEA-AEEA-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIAG GPSSGAPPPS-NH 2 ;
compound 37:
Y-Iva-EGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLD GGPSSGAPPPS-NH 2 ;
compound 38:
Y-Aib-EGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLD GGPSSGAPPPS-NH 2 ;
compound 39:
Y-Iva-EGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLD GGPSSGAPPPS-NH 2 ;
compound 40:
Y-Iva-QGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLD GGPSSGAPPPS-NH 2 ;
compound 41:
Y-Cba-EGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLL DGGPSSGAPPPS-NH 2 ;
compound 42:
Y-Cba-EGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLL DGGPSSGAPPPS-NH 2 ;
compound 43:
Y-Aib-EGTFTSDYSI-Cba-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLL DGGPSSGAPPPS-NH 2 ;
compound 44:
Y-Iva-EGTFTSDYSI-Cba-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLL DGGPSSGAPPPS-NH 2 ;
compound 45:
H-Aib-EGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLA GGPSSGAPPPS-OH;
compound 46:
H-Iva-EGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLA GGPSSGAPPPS-OH;
compound 47:
H-Iva-QGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLA GGPSSGAPPPS-OH;
compound 48:
H-Iva-EGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLA GGPSSGAPPPS-OH;
compound 49:
H-Iva-QGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLD GGPSSGAPPPS-OH;
compound 50:
H-Iva-EGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLLD GGPSSGAPPPS-OH;
compound 51:
H-Cba-QGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLI AGGPSSGAPPPS-OH;
compound 52:
H-Cba-QGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLL DGGPSSGAPPPS-OH;
compound 53:
H-Aib-QGTFTSDYSI-Iva-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIA GGPSSG-Aib-PPPS-OH;
compound 54:
H-(D-Ser)-QGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQ WLLDGGPSSGAPPPS-OH;
compound 55:
Y-Iva-EGTFTS(D)YSI-Iva-LD(K)IAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLI AGGPSSGAPPPS-NH 2 wherein amino acid D at position 9 and amino acid K at position 16 are connected through an amide bond;
compound 56:
Y-Aib-EGTFTS(D)YSI-Iva-LD(K)IAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWL LDGGPSSGAPPPS-NH 2 wherein amino acid D at position 9 and amino acid K at position 16 are connected through an amide bond;
Compound 57:
Y-Iva-EGTFTS(D)YSI-Iva-LD(K)IAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWL LDGGPSSGAPPPS-NH 2 wherein amino acid D at position 9 and amino acid K at position 16 are connected through an amide bond;
compound 58:
H-Aib-QGTFTS(D)YSI-Aib-LD(K)IAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 h) AFVQW LLDGGPSSGAPPPS-OH, wherein amino acid D at position 9 is linked to amino acid K at position 16 by an amide bond;
compound 59:
H-Iva-EGTFTS(D)YSI-Aib-LD(K)IAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 h) AFVQWL LDGGPSSGAPPPS-OH, wherein amino acid D at position 9 is linked to amino acid K at position 16 by an amide bond;
compound 60:
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK(GGSGSGSG-γGlu-CO(CH 2 ) 18 CO 2 H)AFVQWLIA GGPSSGAPPPS-NH 2 。
11. the long-acting polypeptide compound of claim 1, wherein the long-acting polypeptide compound is a pharmaceutically acceptable salt.
12. A composition comprising a long-acting polypeptide compound of any one of claims 1-11 and a pharmaceutically acceptable carrier or adjuvant.
13. Use of a long-acting polypeptide compound of any one of claims 1-11 or a composition of claim 12 in the manufacture of a medicament for the prevention or treatment of diabetes;
alternatively, the use of said long-acting polypeptide compound or said composition in the manufacture of a medicament for the prevention or treatment of obesity.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2022113912306 | 2022-11-07 | ||
CN202211391230 | 2022-11-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117756913A true CN117756913A (en) | 2024-03-26 |
Family
ID=90320736
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310598335.7A Pending CN117756913A (en) | 2022-11-07 | 2023-05-24 | Novel long-acting polypeptide compound, composition and application thereof |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN117756913A (en) |
WO (1) | WO2024098718A1 (en) |
-
2023
- 2023-05-24 CN CN202310598335.7A patent/CN117756913A/en active Pending
- 2023-05-24 WO PCT/CN2023/096029 patent/WO2024098718A1/en unknown
Also Published As
Publication number | Publication date |
---|---|
WO2024098718A1 (en) | 2024-05-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210077629A1 (en) | Improved peptide pharmaceuticals | |
US20180327454A1 (en) | Peptide pharmaceuticals | |
CN111253475B (en) | GLP-1 agonist polypeptide compound and salt thereof, and synthesis method and application thereof | |
CN112409460B (en) | GLP-1/glucagon receptor dual agonist and application thereof | |
CN106928341B (en) | Fixed-point mono-substituted pegylated Exendin analogue and preparation method thereof | |
EP1695983A2 (en) | Glucagon-like peptide-1 analogs | |
JP2022172128A (en) | Improved peptide medicinal drug for insulin resistance | |
KR20210016083A (en) | Improved peptide pharmaceuticals for insulin resistance | |
KR20110043686A (en) | Analogues of glucose-dependent insulinotropic polypeptide | |
KR20140040164A (en) | Improved peptide pharmaceuticals for insulin resistance | |
US20100021480A1 (en) | Bioactive substance-blood protein conjugate and stabilization of a bioactive substance using the same | |
US20070293429A1 (en) | Vasoactive Intestinal Polypeptide Compositions | |
KR20130127985A (en) | Glucose-dependent insulinotropic peptide analogs | |
KR970009353B1 (en) | Superactive human insulin analogues | |
KR20150005904A (en) | Novel gh-rh analogs with potent agonistic effects | |
WO2023000240A1 (en) | Long-acting glp-1 polypeptide analogue, and preparation method therefor and use thereof | |
CN112608378B (en) | GLP-1/cholecystokinin-1 receptor dual agonist and application thereof | |
CN112759640B (en) | GLP-1/gastrin receptor dual agonist and application thereof | |
CN117756913A (en) | Novel long-acting polypeptide compound, composition and application thereof | |
CN115785249B (en) | GLP-1 analogues and application thereof | |
CN116589536B (en) | Long-acting GLP-1/GIP receptor dual agonist and application thereof | |
CN115232200B (en) | Long-acting Exendin-4 analogue and application thereof | |
CN114945589B (en) | Polypeptide compound and application thereof in preventing or treating diabetes or diabetic complications | |
CN114685642B (en) | Pharmaceutically acceptable salt of incretin analogue, and preparation method and application thereof | |
US20220401521A1 (en) | A high-purity adrenocorticotropic hormone analogue and a large-scale preparation method thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |