CN115819551A - 一种定点改造的一类glp-1/胰高血糖素/胃泌素受体三重激动剂及其应用 - Google Patents
一种定点改造的一类glp-1/胰高血糖素/胃泌素受体三重激动剂及其应用 Download PDFInfo
- Publication number
- CN115819551A CN115819551A CN202211173424.9A CN202211173424A CN115819551A CN 115819551 A CN115819551 A CN 115819551A CN 202211173424 A CN202211173424 A CN 202211173424A CN 115819551 A CN115819551 A CN 115819551A
- Authority
- CN
- China
- Prior art keywords
- acid
- ser
- gly
- asp
- pro
- 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
- 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 title claims abstract description 33
- 229960004666 glucagon Drugs 0.000 title claims abstract description 33
- 108010089448 Cholecystokinin B Receptor Proteins 0.000 title claims abstract description 27
- 108010063919 Glucagon Receptors Proteins 0.000 title claims abstract description 20
- 239000013559 triple agonist Substances 0.000 title claims abstract description 18
- 102000052874 Gastrin receptors Human genes 0.000 title claims abstract description 13
- 102100040918 Pro-glucagon Human genes 0.000 title claims abstract description 13
- 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 title claims abstract 12
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 title claims abstract 11
- 230000004048 modification Effects 0.000 title abstract description 9
- 238000012986 modification Methods 0.000 title abstract description 9
- 102400000321 Glucagon Human genes 0.000 title 1
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 107
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 90
- 229920001184 polypeptide Polymers 0.000 claims abstract description 87
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 102000051325 Glucagon Human genes 0.000 claims abstract description 32
- 102000005962 receptors Human genes 0.000 claims description 28
- 108020003175 receptors Proteins 0.000 claims description 28
- 108060003199 Glucagon Proteins 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 22
- 150000001413 amino acids Chemical group 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 208000030159 metabolic disease Diseases 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- HXMVNCMPQGPRLN-UHFFFAOYSA-N 2-hydroxyputrescine Chemical compound NCCC(O)CN HXMVNCMPQGPRLN-UHFFFAOYSA-N 0.000 claims description 4
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 108010019521 carbonic anhydrase VI Proteins 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- 208000016097 disease of metabolism Diseases 0.000 claims description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims description 2
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 claims description 2
- YGTUPRIZNBMOFV-UHFFFAOYSA-N 2-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C=C1 YGTUPRIZNBMOFV-UHFFFAOYSA-N 0.000 claims description 2
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 claims description 2
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 claims description 2
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- AWQSAIIDOMEEOD-UHFFFAOYSA-N 5,5-Dimethyl-4-(3-oxobutyl)dihydro-2(3H)-furanone Chemical compound CC(=O)CCC1CC(=O)OC1(C)C AWQSAIIDOMEEOD-UHFFFAOYSA-N 0.000 claims description 2
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N Camphoric acid Natural products CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 claims description 2
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 claims description 2
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 claims description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- 239000005639 Lauric acid Substances 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 229960001126 alginic acid Drugs 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 150000004781 alginic acids Chemical class 0.000 claims description 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 claims description 2
- 235000013985 cinnamic acid Nutrition 0.000 claims description 2
- 229930016911 cinnamic acid Natural products 0.000 claims description 2
- 229960004106 citric acid Drugs 0.000 claims description 2
- WOWBFOBYOAGEEA-UHFFFAOYSA-N diafenthiuron Chemical compound CC(C)C1=C(NC(=S)NC(C)(C)C)C(C(C)C)=CC(OC=2C=CC=CC=2)=C1 WOWBFOBYOAGEEA-UHFFFAOYSA-N 0.000 claims description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229960002598 fumaric acid Drugs 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- 229950006191 gluconic acid Drugs 0.000 claims description 2
- 235000012208 gluconic acid Nutrition 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098895 maleic acid Drugs 0.000 claims description 2
- 229960002510 mandelic acid Drugs 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 claims description 2
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 claims description 2
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 2
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 claims description 2
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 claims description 2
- 235000001968 nicotinic acid Nutrition 0.000 claims description 2
- 229960003512 nicotinic acid Drugs 0.000 claims description 2
- 239000011664 nicotinic acid Substances 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 229920003175 pectinic acid Polymers 0.000 claims description 2
- 150000004968 peroxymonosulfuric acids Chemical class 0.000 claims description 2
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 claims description 2
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 2
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- 229940107700 pyruvic acid Drugs 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- UJZQBMQZMKFSRV-RGKBJLTCSA-N (2s,3s)-4-[(e)-3-[(1r)-1-carboxy-2-(3,4-dihydroxyphenyl)ethoxy]-3-oxoprop-1-enyl]-2-(3,4-dihydroxyphenyl)-7-hydroxy-2,3-dihydro-1-benzofuran-3-carboxylic acid Chemical compound C([C@H](C(=O)O)OC(=O)\C=C\C=1C=2[C@H](C(O)=O)[C@H](OC=2C(O)=CC=1)C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 UJZQBMQZMKFSRV-RGKBJLTCSA-N 0.000 claims 1
- UJZQBMQZMKFSRV-PHQFMFTGSA-N Lithospermic acid Natural products O([C@@H](C(=O)O)Cc1cc(O)c(O)cc1)C(=O)/C=C/c1c2[C@@H](C(=O)O)[C@H](c3cc(O)c(O)cc3)Oc2c(O)cc1 UJZQBMQZMKFSRV-PHQFMFTGSA-N 0.000 claims 1
- NFOCYHUCMXEHDG-UHFFFAOYSA-N Monomethyl lithospermate Natural products COC(=O)C1C(C=2C=C(O)C(O)=CC=2)OC(C(=CC=2)O)=C1C=2C=CC(=O)OC(C(O)=O)CC1=CC=C(O)C(O)=C1 NFOCYHUCMXEHDG-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- STCJJTBMWHMRCD-UHFFFAOYSA-N salvianolic acid B Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=O)C=Cc2cc(O)c(O)c3OC(C(C(=O)OC(Cc4ccc(O)c(O)c4)C(=O)O)c23)c5ccc(O)c(O)c5 STCJJTBMWHMRCD-UHFFFAOYSA-N 0.000 claims 1
- 102100040890 Glucagon receptor Human genes 0.000 abstract description 12
- 102400000922 Gastrin-6 Human genes 0.000 abstract description 10
- 101800002467 Gastrin-6 Proteins 0.000 abstract description 10
- 239000000556 agonist Substances 0.000 abstract description 10
- 230000001270 agonistic effect Effects 0.000 abstract description 9
- 230000002218 hypoglycaemic effect Effects 0.000 abstract description 5
- 101001040075 Homo sapiens Glucagon receptor Proteins 0.000 abstract description 2
- 230000008901 benefit Effects 0.000 abstract description 2
- 239000011347 resin Substances 0.000 description 38
- 229920005989 resin Polymers 0.000 description 38
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 108010081265 ZP3022 Proteins 0.000 description 23
- 230000000694 effects Effects 0.000 description 22
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 22
- 241000699670 Mus sp. Species 0.000 description 20
- 208000008589 Obesity Diseases 0.000 description 19
- 235000020824 obesity Nutrition 0.000 description 19
- 102400000921 Gastrin Human genes 0.000 description 18
- 108010052343 Gastrins Proteins 0.000 description 17
- 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 17
- 229950011186 semaglutide Drugs 0.000 description 17
- 108010060325 semaglutide Proteins 0.000 description 17
- 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 16
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)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](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)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=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 16
- 108010019598 Liraglutide Proteins 0.000 description 16
- 210000004369 blood Anatomy 0.000 description 16
- 239000008280 blood Substances 0.000 description 16
- 239000008103 glucose Substances 0.000 description 16
- 229960002701 liraglutide Drugs 0.000 description 16
- 206010012601 diabetes mellitus Diseases 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 235000001014 amino acid Nutrition 0.000 description 11
- AOXOCDRNSPFDPE-UKEONUMOSA-N chembl413654 Chemical compound C([C@H](C(=O)NCC(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](C)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@@H](N)CCC(O)=O)C1=CC=C(O)C=C1 AOXOCDRNSPFDPE-UKEONUMOSA-N 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 10
- 102400000319 Oxyntomodulin Human genes 0.000 description 10
- 101800001388 Oxyntomodulin Proteins 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- -1 gastrin compound Chemical class 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 230000009286 beneficial effect Effects 0.000 description 9
- 230000008878 coupling Effects 0.000 description 9
- 238000010168 coupling process Methods 0.000 description 9
- 238000005859 coupling reaction Methods 0.000 description 9
- 238000010511 deprotection reaction Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 8
- 102100032882 Glucagon-like peptide 1 receptor Human genes 0.000 description 8
- 108090000028 Neprilysin Proteins 0.000 description 8
- 102000003729 Neprilysin Human genes 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 235000009200 high fat diet Nutrition 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 230000005847 immunogenicity Effects 0.000 description 7
- 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 7
- 239000000047 product Substances 0.000 description 7
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 7
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 6
- 108010011459 Exenatide Proteins 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- JUFFVKRROAPVBI-PVOYSMBESA-N chembl1210015 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=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](CCCCN)C(=O)N[C@@H](CC(=O)N[C@H]1[C@@H]([C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@]3(O[C@@H](C[C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C3)C(O)=O)O2)O)[C@@H](CO)O1)NC(C)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)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)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 JUFFVKRROAPVBI-PVOYSMBESA-N 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 238000003776 cleavage reaction Methods 0.000 description 6
- 229960001519 exenatide Drugs 0.000 description 6
- CMWYAOXYQATXSI-UHFFFAOYSA-N n,n-dimethylformamide;piperidine Chemical compound CN(C)C=O.C1CCNCC1 CMWYAOXYQATXSI-UHFFFAOYSA-N 0.000 description 6
- 230000007017 scission Effects 0.000 description 6
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 208000016261 weight loss Diseases 0.000 description 6
- 230000004580 weight loss Effects 0.000 description 6
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 5
- 208000001145 Metabolic Syndrome Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 208000033679 diabetic kidney disease Diseases 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 102100025841 Cholecystokinin Human genes 0.000 description 4
- 101800001982 Cholecystokinin Proteins 0.000 description 4
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 4
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 4
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 4
- 210000000577 adipose tissue Anatomy 0.000 description 4
- 229940107137 cholecystokinin Drugs 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 108010036598 gastric inhibitory polypeptide receptor Proteins 0.000 description 4
- 239000003629 gastrointestinal hormone Substances 0.000 description 4
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000010254 subcutaneous injection Methods 0.000 description 4
- 239000007929 subcutaneous injection Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- SJVFAHZPLIXNDH-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=CC=C1 SJVFAHZPLIXNDH-QFIPXVFZSA-N 0.000 description 3
- JDDWRLPTKIOUOF-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl n-[[4-[2-[bis(4-methylphenyl)methylamino]-2-oxoethoxy]phenyl]-(2,4-dimethoxyphenyl)methyl]carbamate Chemical compound COC1=CC(OC)=CC=C1C(C=1C=CC(OCC(=O)NC(C=2C=CC(C)=CC=2)C=2C=CC(C)=CC=2)=CC=1)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JDDWRLPTKIOUOF-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000009514 concussion Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 230000030136 gastric emptying Effects 0.000 description 3
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 210000004923 pancreatic tissue Anatomy 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229940044601 receptor agonist Drugs 0.000 description 3
- 239000000018 receptor agonist Substances 0.000 description 3
- 230000008929 regeneration Effects 0.000 description 3
- 238000011069 regeneration method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- 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 2
- YPTNAIDIXCOZAJ-LHEWISCISA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[[(4-methylphenyl)-diphenylmethyl]amino]hexanoic acid Chemical compound C1=CC(C)=CC=C1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)NCCCC[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 YPTNAIDIXCOZAJ-LHEWISCISA-N 0.000 description 2
- IXHPIPUIOSSAIS-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]imidazol-4-yl]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CN(C(=O)OC(C)(C)C)C=N1 IXHPIPUIOSSAIS-NSHDSACASA-N 0.000 description 2
- 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 2
- XQPYRJIMPDBGRW-UHFFFAOYSA-N 2-[2-[2-(9h-fluoren-9-ylmethoxycarbonylamino)ethoxy]ethoxy]acetic acid Chemical compound C1=CC=C2C(COC(=O)NCCOCCOCC(=O)O)C3=CC=CC=C3C2=C1 XQPYRJIMPDBGRW-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 101800000221 Glucagon-like peptide 2 Proteins 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 102000035554 Proglucagon Human genes 0.000 description 2
- 108010058003 Proglucagon Proteins 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 235000012631 food intake Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- TWSALRJGPBVBQU-PKQQPRCHSA-N glucagon-like peptide 2 Chemical compound C([C@@H](C(=O)N[C@H](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]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O)[C@@H](C)CC)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 TWSALRJGPBVBQU-PKQQPRCHSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- PXZWGQLGAKCNKD-DPNMSELWSA-N molport-023-276-326 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(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)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 PXZWGQLGAKCNKD-DPNMSELWSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000009696 proliferative response Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 238000012430 stability testing Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- 238000004260 weight control Methods 0.000 description 2
- CUXYLFPMQMFGPL-UHFFFAOYSA-N (9Z,11E,13E)-9,11,13-Octadecatrienoic acid Natural products CCCCC=CC=CC=CCCCCCCCC(O)=O CUXYLFPMQMFGPL-UHFFFAOYSA-N 0.000 description 1
- WDUQJXKBWRNMKI-UHFFFAOYSA-N 18-[(2-methylpropan-2-yl)oxy]-18-oxooctadecanoic acid Chemical compound CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(O)=O WDUQJXKBWRNMKI-UHFFFAOYSA-N 0.000 description 1
- INAPMGSXUVUWAF-UOTPTPDRSA-N 1D-myo-inositol 1-phosphate Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](OP(O)(O)=O)[C@H](O)[C@@H]1O INAPMGSXUVUWAF-UOTPTPDRSA-N 0.000 description 1
- 102400000948 Big gastrin Human genes 0.000 description 1
- 101800000285 Big gastrin Proteins 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 1
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 210000000712 G cell Anatomy 0.000 description 1
- 102400000920 Gastrin-14 Human genes 0.000 description 1
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 1
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 1
- 101000788682 Homo sapiens GATA-type zinc finger protein 1 Proteins 0.000 description 1
- 101001015516 Homo sapiens Glucagon-like peptide 1 receptor Proteins 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000003071 IP-One HTRF Assay Methods 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000023178 Musculoskeletal disease Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 241000269368 Xenopus laevis Species 0.000 description 1
- 108010076089 accutase Proteins 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- CUXYLFPMQMFGPL-SUTYWZMXSA-N all-trans-octadeca-9,11,13-trienoic acid Chemical compound CCCC\C=C\C=C\C=C\CCCCCCCC(O)=O CUXYLFPMQMFGPL-SUTYWZMXSA-N 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 238000007681 bariatric surgery Methods 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013118 diabetic mouse model Methods 0.000 description 1
- 229940125542 dual agonist Drugs 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000030135 gastric motility Effects 0.000 description 1
- 108010066264 gastrin 17 Proteins 0.000 description 1
- SSBRJDBGIVUNDK-QOGDCIHTSA-N gastrin-14 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CC=C(O)C=C1 SSBRJDBGIVUNDK-QOGDCIHTSA-N 0.000 description 1
- GKDWRERMBNGKCZ-RNXBIMIWSA-N gastrin-17 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 GKDWRERMBNGKCZ-RNXBIMIWSA-N 0.000 description 1
- FMIHGWZLPSIAFY-WGFKALLTSA-N gastrin-34 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCC(N)=O)C(C)C)C1=CC=C(O)C=C1 FMIHGWZLPSIAFY-WGFKALLTSA-N 0.000 description 1
- 208000004104 gestational diabetes Diseases 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- 108091005995 glycated hemoglobin Proteins 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 102000045598 human DPP4 Human genes 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000006662 intracellular pathway Effects 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000013227 male C57BL/6J mice Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 108010076432 minigastrin Proteins 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000009707 neogenesis Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 230000004203 pancreatic function Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000034918 positive regulation of cell growth Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 208000037920 primary disease Diseases 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 235000018770 reduced food intake Nutrition 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Images
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明提供了一种定点改造的一类GLP‑1/胰高血糖素/胃泌素受体三重激动剂及其应用。本发明的GLP‑1/glucagon/gastrin受体三重激动多肽化合物在更为有效的降低血糖的同时具有更优异的促进胰腺组织的细胞增殖和胰岛再生作用,同时多肽化合物具有优异的减重作用,本发明这个序列的Xaa4和Xaa5,是两个OEG连接臂,然后Tyr‑Gly‑Trp‑Leu‑Asp‑Phe‑NH2是gastrin‑6的结构,与现有专利相比,这个化合物是在GLP‑1/GCGR双激动剂的基础上,在C端继续引入了gastrin‑6的序列,赋予化合物CCK‑2受体的激动活性,从而进一步提高化合物的降糖活性。
Description
技术领域
本发明涉及生物医药领域,具体为了一种定点改造的一类GLP-1/胰高血糖素/胃泌素受体三重激动剂及其应用。
背景技术
肥胖及其相关代谢综合征已成为全球性的公众健康问题,许多代谢综合征如2型糖尿病(T2DM)、非酒精性脂肪肝病(NAFLD)、非酒精性脂肪肝炎 (NASH)、血脂代谢异常的发病率与病程发展都与肥胖密切相关。研究表明,临床上80-90%的T2DM患者伴有超重或肥胖,使用减重疗法有利于预防和控制病情,包括控制血糖、减少患病率和致残(死)率等。仅靠锻炼和饮食控制来减轻体重,一般很难达到理想的减重效果。目前治疗肥胖的药物疗效较为有限,许多治疗肥胖的药物还具有较显著的副作用,如作用于中枢神经引起的精神症状和严重的心血管影响等副作用。在治疗T2DM的药物中,仅有胰高血糖素样肽(GLP-1)受体激动剂和钠-葡萄糖共转运蛋白2(SGLT2)抑制剂具有较好的体重控制效果(J.Med.Chem.,2018,61,5580-5593)。减肥手术对肥胖的治疗效果显著,但是患者所遭受的手术风险较大,并且手术的长期效应仍不明确。因此,用于体重控制的药物目前仍存在巨大的临床需求,能够安全有效地控制体重兼具原发病症治疗作用的药物是理想的选择。
机体的能量和血糖调节信号***包括多种不同的多肽类内源性胃肠道激素,胰高血糖素原(proglucagon)是一种具有160个氨基酸的前体多肽,其在不同组织中裂解后转化为不同的产物,诸如GLP-1、胰高血糖素样肽-2(GLP-2)、胰高血糖素(Glucagon)及胃泌酸调节素(Oxyntomodulin,OXM)等内源性胃肠道激素。这些内源性胃肠道激素参与胰岛素分泌、食物摄取、胃排空以及葡萄糖体内平衡等多种生理功能的调节。因此,基于内源性胃肠道激素的疗法已成为代谢综合征研究领域深受关注的研究方向。
OXM是人体内的一种内源性GLP-1受体和glucagon受体双重激动剂,其对GLP-1受体和glucagon受体的激动活性效力弱于各受体的天然配体(天然 GLP-1或glucagon)。OXM的急性生理作用包括抑制胃排空、摄食以及胃和胰腺的外分泌、提升静息能量消耗等,可产生体重减轻作用。实验表明,在动物和人体内外周给予OXM可减轻体重和降低摄食量,在肥胖对象中可提高代谢率以及和活动相关的能量消耗。此外,在临床中OXM大剂量给药在减轻体重的同时不易发生恶心、呕吐等常见胃肠道副作用。上述实验证实了基于OXM或 GLP-1/glucagon受体双重激动剂的疗法对代谢综合征的治疗显示了潜在的应用价值。
目前已报道的多肽类GLP-1/glucagon受体双重激动剂,按序列结构可以分为基于glucagon、OXM、GLP-1或毒蜥外泌肽-4(exendin-4)四类,已公开的专利文件有:CN201911103118.6、CN201780013643.1、CN201680021972.6、 CN201580030150.X、CN201380048137.8、WO2008/071972、WO 2008/101017、 WO 2009/155258、WO 2010/096052、WO 2010/096142、WO2011/075393、WO 2008/152403、WO 2010/070251、WO 2010/070252、WO2010/070253、 WO2010/070255、WO 2011/160630、WO 2011/006497、WO 2011/087671、WO2011/087672、WO2011/117415、WO2011/117416、WO 2012/177443、WO 2012/177444、WO2012/150503、WO2013/004983、WO 2013/092703、WO 2014/041195和WO 2014/041375等。
两栖动物体内的GLP-1作用效果与人GLP-1类似,所以针对两栖动物GLP-1 进行结构修饰,有望发现具有更高效和长效降糖作用的新型GLP-1类药物。 XenGLP-1是从非洲爪蟾体内发现的一类动物源属的GLP-1类似物,与天然 GLP-1相比,XenGLP-1的降糖活性和稳定性更优。此外,与GLP-1、OXM和 glucagon相比,除了更为耐受二肽基肽酶(DPP-IV)的降解,XenGLP-1还显示出对于中性内肽酶(NEP)的降解稳定得多。XenGLP-1是GLP-1受体的高效激动剂,然而其不会激活glucagon受体。XenGLP-1具有许多用天然GLP-1观察到的葡萄糖调控作用,许多临床前研究都显示XenGLP-1具有若干有益的抗糖尿病特性,包括血糖依赖性的胰岛素合成和分泌增强、胃排空放慢、食物摄入和体重减少,以及促进β细胞增殖和恢复胰岛功能等(Biochem.Pharmacol.,2017, 142,155–167;FASEB J.,2019,33,7113-7125)。这些效果不仅对于糖尿病人是有益的,并且对罹患肥胖症的患者也是有益的。患有肥胖者的患者具有更高的患上高血压、高血脂、糖尿病、NAFLD、NASH、肌肉骨骼和心血管疾病的风险。
胃泌素(gastrin)是由胃粘膜细胞和十二指肠G细胞分泌的,它在人体的主要生理作用是刺激胃酸分泌和帮助胃运动。Gastrin的其他作用包括刺激细胞生长,有迹象表明gastrin可能在胰岛新生中起作用,即刺激胰岛中分泌胰岛素的β细胞生长(见Korc,M.,J.Clin.Invest.,1993,92,1113-1114;Rooman et al. Diabetes,2002,51,686-690),因此有助于调节血糖。Gastrin和另一种胃肠道激素胆囊收缩素(Cholecystokinin,CCK)共享受体,它们的受体分为两类,CCK-1 受体和CCK-2受体(gastrin受体),这两种受体对gastrin和CCK类似物具有不同的亲和力。CCK-1受体主要作为硫酸化CCK的受体,而CCK-2受体对CCK和gastrin具有类似的亲和力。其中CCK-2受体也被认为是gastrin受体,因为血浆中gastrin水平高于CCK(Foucaud et al.Reg.Peptides,2008,145,17-23)。
CCK-2受体与配体结合时可启动多种细胞内通路,CCK-2受体下游的一个关键途径是MAPK(丝裂原活化蛋白激酶)或ERK(胞外调节激酶)通路,这些通路也被几种生长激素激活,这是gastrin在细胞增殖作用中的一个关键特征。由于CCK-2受体在胰腺中表达,gastrin能够促进胰腺组织的细胞增殖和胰岛再生。Gastrin在人体内主要以三种形式存在,按氨基酸数目可分为gastrin-34、 gastrin-17和gastrin-14,此外,还存在一种短肽形式,即gastrin-6。Gastrin-6的 6个氨基酸是gastrin与CCK-2受体结合的关键氨基酸,并且其C端是酰胺化形式。
WO2005/072045公开了一种“GLP-1受体激动剂”和“gastrin化合物”的组合,在预防和/或治疗“GLP-1受体激动剂”或“gastrin化合物”已被证明具有治疗效果的条件和/或疾病中具有有益效果。WO2007/095737公开了“Exendin-4”和“gastrin化合物”的类似组合,在预防和/或治疗“Exendin-4 激动剂”或“gastrin化合物”已被证明具有治疗效果的条件和/或疾病中同样具有有益效果。应注意,WO2005/072045或WO2007/095737均未提供任何体内、体外或其他数据来证实其中分别描述和使用的“GLP-1受体激动剂”/“gastrin 化合物”或“Exendin-4”/“gastrin化合物”组合可能有益于例如类型的治疗 T2DM。US10406207B2公开了一种exendin-4的截短形式和gastrin-6的缀合肽 (ZP3022),K.Fosgerau等揭示了ZP3022在糖尿病模型小鼠中展现出了提高的治疗活性,由于没有长效化修饰,这种缀合肽的半衰期较短,必须频繁注射 (Diabetes Obes Metab.,2013,15,62-71)。此外,ZP3022的减重作用较为薄弱,对于糖尿病合并肥胖患者来说,同时能够显著降糖和减重的药物能够实现更好的治疗效果。Xinyu Chen等揭示了一类XenGLP-1与gastrin-6的缀合肽,但是,该类缀合肽所需修饰手段涉及到多种氨基酸替换,所带来的化合物的免疫原性问题较为显著(J.Med.Chem.2020,63,12595-12613)。并且该类化合物也和 ZP3022存在类似的减重作用不足的问题。
发明内容
本发明的目的是提供一种定点改造的一类GLP-1/胰高血糖素/胃泌素受体三重激动剂及其应用,所述多肽是基于XenGLP-1序列设计的变体,可以同时激动 GLP-1受体、glucagon受体和gastrin受体,进一步提高了XenGLP-1的减重和糖尿病的治疗作用。该类多肽化合物性质稳定,免疫原性低,可以实现一天一次或一周一次给药。同时多肽化合物具有优异的减重作用,比单一受体激动剂和已报道GLP-1/glucagon和GLP-1/gastrin受体双重激动剂在制备用于治疗代谢综合征,诸如糖尿病、肥胖、NAFLD、NASH等疾病的药物方面更具潜力。
为实现上述发明目的,本发明的技术方案具体如下:
一类GLP-1/glucagon/gastrin受体三重激动多肽化合物,该类GLP-1受体、glucagon受体和gastrin受体三重激动多肽化合物的氨基酸序列通式为: His-Xaa1-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Xaa2-Tyr-Xaa3-Asp-Ser-Arg-Arg- Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-P ro-Ser-Xaa4-Xaa5-Tyr-Gly-Trp-Leu-Asp-Phe-NH2
其中:
Xaa1取自Aib,Ser或D-Ser;
Xaa2取自Lys或侧链被修饰的Lys;
Xaa3取自Leu、Lys或侧链被修饰的Lys;
Xaa4取自AEEA或不存在;
Xaa5取自AEEA或不存在;
其中,侧链被修饰的Lys是Lys(γ-Glu-CO-(CH2)n-CH3)或 Lys(AEEA-AEEA-γ-Glu-CO-(CH2)n-COOH),Lys(γ-Glu-CO-(CH2)n-CH3)的结构式如下式所示:
Lys(AEEA-AEEA-γ-Glu-CO-(CH2)n-COOH)的结构式如下式所示:
其中,n为自然数,且12≤n≤20。
优选的,所述n是14、16、18或20。
优选的,所述多肽化合物的氨基酸序列是下列序列之一:
(1)SEQ ID NO:1
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Al a-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro- Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH2;
(2)SEQ ID NO:2
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys-Asp-Ser-Arg-Arg-Al a-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro- Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH2;
(3)SEQ ID NO:3
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-T yr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-S er-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH2;
(4)SEQ ID NO:4
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(C H2)16-COOH)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-As n-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-As p-Phe-NH2;
(5)SEQ ID NO:5
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(γ-Glu-CO-(CH2)14 -CH3)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-S er-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH2;
(6)SEQ ID NO:6
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(AEEA-AEEA-γ-Gl u-CO-(CH2)16-COOH)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-As n-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH2。
本发明还提供了一类GLP-1/glucagon/gastrin受体三重激动多肽化合物药学上可接受的盐。
优选的,所述的盐为GLP-1/glucagon/gastrin受体三重激动多肽化合物与下述化合物中的一种所形成的盐:氢溴酸、盐酸、甲磺酸、磷酸、乙磺酸、甲酸、对甲苯磺酸、乙酸、乙酰乙酸、丙酮酸、果胶酯酸、丁酸、己酸、苯磺酸、庚酸、十一烷酸、苯甲酸、水杨酸、月桂酸、2-(4-羟基苯甲酰基)苯甲酸、肉桂酸、樟脑酸、环戊烷丙酸、3-羟基-2-萘甲酸、樟脑磺酸、二葡糖酸、烟酸、扑酸、丙酸、过硫酸、苦味酸、3-苯基丙酸、特戊酸、衣康酸、2-羟基乙磺酸、氨基磺酸、十二烷基硫酸、三氟甲磺酸、萘二磺酸、2-萘磺酸、柠檬酸、扁桃酸、抗坏血酸、酒硬脂酸、石酸、草酸、乳酸、琥珀酸、丙二酸、半硫酸、苹果酸、马来酸、藻酸、富马酸、D-葡糖酸、甘油磷酸、葡庚酸、天冬氨酸、硫氰酸或者磺基水杨酸。
本发明还提供了GLP-1/glucagon/gastrin受体三重激动多肽化合物的药物组合物,该药物组合物包括:以上述任一GLP-1/glucagon/gastrin受体三重激动多肽化合物或其药学上可接受的盐为有效原料,再加上药学上可接受的载体或稀释剂组成。
本发明还提供了含有上述GLP-1/glucagon/gastrin受体三重激动多肽化合物的药剂,所述的药剂是任何一种药剂学上所说的胶囊、片剂、喷雾剂、吸入剂、注射剂、贴剂、乳剂、膜剂、散剂或者复方制剂,药剂由GLP-1/glucagon/gastrin 受体三重激动多肽化合物和药学上可接受的药用辅料、载体或稀释剂组成。
本发明还提供了本发明所述的GLP-1/glucagon/gastrin受体三重激动多肽化合物、其药学上可接受的盐、其药物组合物或其药剂在制备用于治疗代谢性疾病或病症的药物中的应用。在特定方面,代谢性疾病或病症为糖尿病、糖尿病肾病、NAFLD、NASH或肥胖。在特定方面,糖尿病为1型糖尿病、T2DM或妊娠糖尿病。在特定方面,所述药物用于治疗超过一种代谢疾病或病症,例如,糖尿病和NAFLD、NASH或肥胖;糖尿病肾病和NAFLD、NASH或肥胖;肥胖和NASH或NAFLD;糖尿病、NASH和肥胖;糖尿病、NAFLD和肥胖;或糖尿病和肥胖。
与现有技术相比,本发明的有益效果:
本发明这个序列的Xaa4和Xaa5,是两个OEG连接臂,然后Tyr-Gly-Trp-Leu-Asp-Phe-NH2是gastrin-6的结构,与现有专利相比,这个化合物是在GLP-1/GCGR双激动剂的基础上,在C端继续引入了gastrin-6的序列,赋予化合物CCK-2受体的激动活性,从而进一步提高化合物的降糖活性。
因此也与现有的GLP-1受体激动剂相比,本发明的GLP-1/glucagon/gastrin 受体三重激动多肽化合物在更为有效的降低血糖和体重的同时具有更优异的促进胰腺组织的细胞增殖和胰岛再生作用,可以从根本上治疗糖尿病,逆转胰岛素抵抗,治疗糖尿病肾病并发症,与现有药物相比具有意想不到的有益作用。本发明的多肽化合物对GLP-1受体、glucagon受体和gastrin受体的激动活性高于各受体的天然配体,本发明提供的多肽化合物化学性质稳定,不易被体内的 DPP-IV和NEP降解,不易被肾小球滤过,化合物的稳定性显著提高,具有支持每天一次和每周一次给药的药代动力学特征。本发明提供的多肽化合物具有提高的生物物理特性,在中性pH和pH 4.5的溶解性都高于天然GLP-1、glucagon 和gastrin-6,具备有利于制剂的特性。本发明提供的多肽化合物具有低的免疫原性特性,更优异的降血糖活性和减重作用,对T2DM、肥胖、糖尿病肾病、NAFLD、 NASH等代谢性疾病的治疗作用优于现有上市药物。因此,本发明提供的多肽化合物,适合作为治疗代谢性疾病,如糖尿病、肥胖、糖尿病肾病、NAFLD、 NASH等药物的活性成分。
应当理解,前述构思以及在下面更加详细地描述的额外构思的所有组合只要在这样的构思不相互矛盾的情况下都可以被视为本公开的发明主题的一部分。
结合附图从下面的描述中可以更加全面地理解本发明教导的前述和其他方面、实施例和特征。本发明的其他附加方面例如示例性实施方式的特征和/或有益效果将在下面的描述中显见,或通过根据本发明教导的具体实施方式的实践中得知。
附图说明
图1显示的是各受试物在体外的免疫原性。
具体实施方式
为了更了解本发明的技术内容,特举具体实施例并配合所附图式说明如下。在本公开中参照附图来描述本发明的各方面,附图中示出了许多说明的实施例。本公开的实施例不必定义在包括本发明的所有方面。应当理解,上面介绍的多种构思和实施例,以及下面更加详细地描述的那些构思和实施方式可以以很多方式中任意一种来实施,这是因为本发明所公开的构思和实施例并不限于任何实施方式。另外,本发明公开的一些方面可以单独使用,或者与本发明公开的其他方面的任何适当组合来使用。
实施例1SEQ ID NO:1多肽化合物的合成
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Ar g-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro -Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH2;
(1)树脂的溶胀
称取担载量为0.382mmol/g的Rink Amide MBHA树脂0.262g(0.1mmol 当量),放入25mL的反应器中,用7mL的DCM和甲醇交替清洗树脂1次,7 mL的DCM清洗树脂2次,然后用7mL的DCM溶胀树脂1h,最后用7mL DMF 清洗树脂3次。
(2)树脂Fmoc保护基的脱除
将溶胀后的树脂转入PSI200多肽合成仪,加入7mL 20%哌啶/DMF(v/v) 室温反应5min,滤去脱保护溶液,7mL DMF清洗树脂一次,再加入7mL 20%哌啶/DMF(v/v)脱保护溶剂与树脂反应15min,最后7mL DMF清洗树脂4次,每次1.5min,得到脱除Fmoc保护基的Rink树脂。
(3)Fmoc-Phe-Rink amide-MBHA Resin的合成
称Fmoc-Phe-OH(0.4mmol),用3mL 10%DMF/DMSO(v/v)溶解,加入 2mL DIC/HOBt(0.4mmol/0.44mmol)缩合剂,预活化30min后,将活化好的氨基酸加入反应器中,室温震荡反应2h,滤去反应液后用7mL DMF清洗树脂 4次,使用Kaiser试剂检测反应耦合是否完全,如不完全则2次耦合。
(4)肽链的延长
按照肽链的序列,重复上述脱保护和耦合的步骤依次连接上相应的氨基酸,直至肽链合成完毕。
(5)多肽的裂解
将上述得到的连有多肽的树脂转移至圆底瓶中,使用切割剂Reagent R(TFA/ 苯甲硫醚/苯酚/EDT,90:5:3:2,V/V)5mL切割树脂,在油浴中恒温30℃反应 2h,切割液倾入40mL冰***中,冷冻离心后粗品用15mL冰***洗涤3次,最后用氮气吹干,得到粗肽。
(6)多肽的纯化
将目标多肽粗品溶于水中,用0.25μm微孔滤膜过滤后进岛津制备型反相 HPLC***纯化。色谱条件为C18反相制备柱(250mm×20mm,12μm);流动相A:0.1%TFA/水(V/V),流动相B:甲醇(V/V);流速为8mL/min;检测波长为214nm。采用线性梯度(20%B~80%B/30min)洗脱,收集目标峰,除去甲醇后冻干得纯品0.26g,纯度大于98%,通过LC-MS确认目标多肽的分子量。
实施例2SEQ ID NO:2多肽化合物的合成
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys-Asp-Ser-Arg-Ar g-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro -Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH2;
合成方法同实施例1,收集目标峰冻干得纯品0.23g。
实施例3SEQ ID NO:3多肽化合物的合成
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH2 ;
(1)树脂的溶胀
称取担载量为0.382mmol/g的Rink Amide MBHA树脂0.262g(0.1mmol 当量),放入25mL的反应器中,用7mL的DCM和甲醇交替清洗树脂1次,7 mL的DCM清洗树脂2次,然后用7mL的DCM溶胀树脂1h,最后用7mL DMF 清洗树脂3次。
(2)树脂Fmoc保护基的脱除
将溶胀后的树脂转入PSI200多肽合成仪,加入7mL 20%哌啶/DMF(v/v) 室温反应5min,滤去脱保护溶液,7mL DMF清洗树脂一次,再加入7mL 20%哌啶/DMF(v/v)脱保护溶剂与树脂反应15min,最后7mL DMF清洗树脂4次,每次1.5min,得到脱除Fmoc保护基的Rink树脂。
(3)Fmoc-Phe-Rink amide-MBHA Resin的合成
称Fmoc-Phe-OH(0.4mmol),用3mL 10%DMF/DMSO(v/v)溶解,加入 2mL DIC/HOBt(0.4mmol/0.44mmol)缩合剂,预活化30min后,将活化好的氨基酸加入反应器中,室温震荡反应2h,滤去反应液后用7mL DMF清洗树脂 4次,使用Kaiser试剂检测反应耦合是否完全,如不完全则2次耦合。
(4)肽链的延长
按照肽链的序列,重复上述脱保护和耦合的步骤依次连接上相应的氨基酸,直至肽链合成完毕。其中12位Lys可以采用Fmoc-Lys(Alloc)-OH、 Fmoc-Lys(Dde)-OH、Fmoc-Lys(Mtt)-OH或Fmoc-Lys(ivDde)-OH等。本实例中采用Fmoc-Lys(Dde)-OH保护策略,同时N末端的His使用的是Boc-His(Boc)-OH。
(5)Lys侧链的修饰
肽链合成完毕后,加入7mL 2%水合肼/DMF(v/v)选择性脱除12位Lys 的Dde保护基,Dde保护基脱除后加入0.4mmol的Fmoc-Glu-OtBu,0.4mmol的 DIC及0.44mmol的HOBt,震荡反应2h。然后使用上述相同方法脱除Fmoc 保护基后,加入0.4mmol的棕榈酸,0.4mmol的DIC及0.44mmol的HOBt 缩合反应2h,反应完全后用7mL DMF清洗树脂4次。
(6)多肽的裂解
将上述得到的连有多肽的树脂转移至圆底瓶中,使用切割剂Reagent R(TFA/ 苯甲硫醚/苯酚/EDT,90:5:3:2,V/V)5mL切割树脂,在油浴中恒温30℃反应 2h,切割液倾入40mL冰***中,冷冻离心后粗品用15mL冰***洗涤3次,最后用氮气吹干,得到粗肽。
(7)多肽的纯化
将目标多肽粗品溶于水中,用0.25μm微孔滤膜过滤后进岛津制备型反相 HPLC***纯化。色谱条件为C18反相制备柱(250mm×20mm,12μm);流动相A:0.1%TFA/水(V/V),流动相B:甲醇(V/V);流速为8mL/min;检测波长为214nm。采用线性梯度(20%B~70%B/30min)洗脱,收集目标峰,除去甲醇后冻干得纯品0.29g,纯度大于98%,通过LC-MS确认目标多肽的分子量。
实施例4SEQ ID NO:4多肽化合物的合成
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-L ys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-L eu-Asp-Phe-NH2;
(1)树脂的溶胀
称取担载量为0.382mmol/g的Rink Amide MBHA树脂0.262g(0.1mmol 当量),放入25mL的反应器中,用7mL的DCM和甲醇交替清洗树脂1次,7 mL的DCM清洗树脂2次,然后用7mL的DCM溶胀树脂1h,最后用7mL DMF 清洗树脂3次。
(2)树脂Fmoc保护基的脱除
将溶胀后的树脂转入PSI200多肽合成仪,加入7mL 20%哌啶/DMF(v/v) 室温反应5min,滤去脱保护溶液,7mL DMF清洗树脂一次,再加入7mL 20%哌啶/DMF(v/v)脱保护溶剂与树脂反应15min,最后7mL DMF清洗树脂4次,每次1.5min,得到脱除Fmoc保护基的Rink树脂。
(3)Fmoc-Phe-Rink amide-MBHA Resin的合成
称Fmoc-Phe-OH(0.4mmol),用3mL 10%DMF/DMSO(v/v)溶解,加入 2mL DIC/HOBt(0.4mmol/0.44mmol)缩合剂,预活化30min后,将活化好的氨基酸加入反应器中,室温震荡反应2h,滤去反应液后用7mL DMF清洗树脂 4次,使用Kaiser试剂检测反应耦合是否完全,如不完全则2次耦合。
(4)肽链的延长
按照肽链的序列,重复上述脱保护和耦合的步骤依次连接上相应的氨基酸,直至肽链合成完毕。其中12位Lys可以采用Fmoc-Lys(Alloc)-OH、 Fmoc-Lys(Dde)-OH、Fmoc-Lys(Mtt)-OH或Fmoc-Lys(ivDde)-OH等。本实例中采用Fmoc-Lys(Dde)-OH保护策略,同时N末端的His使用的是Boc-His(Boc)-OH。
(5)Lys侧链的修饰
肽链合成完毕后,加入7mL 2%水合肼/DMF(v/v)选择性脱除12位Lys 的Dde保护基,Dde保护基脱除后加入0.4mmol的Fmoc-AEEA-OH,0.4mmol 的DIC及0.44mmol的HOBt,震荡缩合反应2h。脱除Fmoc保护基后,再次加入0.4mmol的Fmoc-AEEA-OH,0.4mmol的DIC及0.44mmol的HOBt,震荡缩合反应2h。脱除Fmoc保护基后,加入0.4mmol的Fmoc-Glu-OtBu,0.4mmol 的DIC及0.44mmol的HOBt,震荡缩合反应2h。脱除Fmoc保护基后,加入 0.4mmol的十八烷二酸单叔丁酯,0.4mmol的DIC及0.44mmol的HOBt缩合反应2h,反应完全后用7mL DMF清洗树脂4次。
(6)多肽的裂解
将上述得到的连有多肽的树脂转移至圆底瓶中,使用切割剂Reagent R(TFA/ 苯甲硫醚/苯酚/EDT,90:5:3:2,V/V)5mL切割树脂,在油浴中恒温30℃反应 2h,切割液倾入40mL冰***中,冷冻离心后粗品用15mL冰***洗涤3次,最后用氮气吹干,得到粗肽。
(7)多肽的纯化
将目标多肽粗品溶于水中,用0.25μm微孔滤膜过滤后进岛津制备型反相 HPLC***纯化。色谱条件为C18反相制备柱(250mm×20mm,12μm);流动相A:0.1%TFA/水(V/V),流动相B:甲醇(V/V);流速为8mL/min;检测波长为214nm。采用线性梯度(20%B~80%B/30min)洗脱,收集目标峰,除去甲醇后冻干得纯品0.27g,纯度大于98%,通过LC-MS确认目标多肽的分子量。
实施例5SEQ ID NO:5多肽化合物的合成
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(γ-Glu-CO-(CH 2)14-CH3)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-P ro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH2;
合成方法同实施例3,收集目标峰冻干得纯品0.23g。
实施例6SEQ ID NO:6多肽化合物的合成
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-L ys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-L eu-Asp-Phe-NH2;
合成方法同实施例4,收集目标峰冻干得纯品0.26g。
实施例7多肽化合物对GLP-1受体、glucagon受体、GIP受体、CCK-1受体和CCK-2受体的激动活性测定
通过功能测定法来确定多肽化合物对受体的激动作用,所述测定法测量稳定表达人GLP-1受体、glucagon受体或GIP受体的HEK-293细胞系的cAMP响应。将稳定表达上述三种受体的细胞分入T175培养瓶并在培养基(DMEM/10% FBS)中过夜生长至接近汇合状态,然后除去培养基,并用无钙和镁的PBS洗涤细胞,然后用Accutase酶进行蛋白酶处理。洗涤脱离的细胞并将其重悬于测定缓冲液(20mM HEPES,0.1%BSA,2mM IBMX,1×HBSS)中,并确定细胞密度,并将25μL的等分试样分装至96孔板的孔中。为了测量,将25μL的测试多肽化合物在测定缓冲液中的溶液添加到孔中,然后室温温育30分钟。用 Cisbio的试剂盒,基于均相时间分辨荧光(HTRF)来确定细胞的cAMP含量。添加稀释于裂解缓冲液(试剂盒组分)中的HTRF试剂后,将平板温育1小时,然后测量665/620nm处的荧光比。通过检测引起最大响应的50%激活的浓度 (EC50)来对激动剂的体外效力进行量化。
稳定表达CCK-1受体或CCK-2受体的1321-N1细胞用DMEM-31966(含有10%FBS,1%丙酮酸钠,1%青霉素,1%链霉素)培养。试验前一天,将细胞转移至384孔板中,化合物溶解在IP-One缓冲溶液中(含有10mmol/L HEPES, 1mmol/L CaCl2,4.2mmol/L KCl,146mmol/LNaCl,5.5mmol/L葡萄糖,50 mmol/L LiCl)并稀释,加入384孔板中。在37℃孵育1小时后,使用IP-One HTRF Assay kit测定细胞内的1-磷酸肌醇浓度,通过检测引起最大响应的50%激活的浓度(EC50)来对激动剂的体外效力进行量化。
将本专利申请实施例中的检测数据(nM)显示于下表1中,虽然用一定数量的有效数字来陈述检测数据,但不应该认为表示数据已确定精确为有效数字的数。
表1:多肽化合物对GLP-1受体、glucagon受体、GIP受体CCK-1受体和 CCK-2受体(gastrin受体)的EC50值(以nM表示)
如表1所示,所有多肽化合物对GLP-1受体的激动活性都高于天然GLP-1 和ZP3022,并且部分多肽化合物对glucagon受体的激动活性也高于天然 glucagon,所有多肽化合物对CCK-2受体的激动活性也高于gastrin-6和ZP3022,所有多肽化合物都表现出了CCK-2受体激动的高选择性,选择性明显优于 gastrin-6和ZP3022,同时所有多肽化合物都表现出了更弱的GIP受体的激动活性。
实施例8多肽化合物的溶解度和稳定性测试
在测试多肽化合物的溶解度和稳定性之前,首先使用HPLC确定其纯度。然后,基于确定的%纯度,在不同的缓冲体系中,溶解10mg多肽化合物在1mL 溶液中,温和搅拌2小时。使用4500rpm离心20分钟后,取上清液进HPLC 分析,确定峰面积。然后与相应样品标准溶液比对,计算得到受试样品溶液的相对浓度。对于稳定性测试,将溶解度获得的上清液的等分试样在40℃储存7 天,然后样品在4500rpm离心20分钟,上清液进HPLC分析,确定峰面积。通过比较稳定性实验开始前的峰面积(t0)和存储7天后的峰面积(t7),得到“%剩余肽”。按以下公式计算:%剩余肽=[(峰面积t7)×100]/峰面积t0,稳定性表示为“%剩余肽”,计算结果如下表2所示。
表2:多肽化合物的溶解度和稳定性
如表2结果显示,本发明的多肽化合物与天然GLP-1,glucagon,gastrin-6 和ZP3022相比,在机体可接受的注射液pH条件下的溶解性大幅改善,具备了有利于制剂的特性。本发明的多肽化合物在pH 4.5也具有高溶解性,该特性可能允许用于与胰岛素或胰岛素衍生物的组合治疗的共制剂。此外,在pH 4.5和中性pH条件下本发明的多肽化合物也具有更好的稳定性。
实施例9多肽化合物对DPP-IV和NEP酶的稳定性
受试样品于37℃与纯化的人DPP-IV或NEP酶共孵0,2,4,8小时,使用 HPLC法测定各时间点溶液中的残留样品峰面积,计算样品半衰期,结果如表3 所示。
表3:多肽化合物在DPP-IV酶或NEP酶体系中的半衰期(以h表示)
如表3结果显示,本发明的多肽化合物在含DPP-IV酶溶液和NEP酶溶液体系中的半衰期均超过8个小时,优于天然GLP-1、glucagon和ZP3022,说明可以有效耐受DPP-IV和NEP酶的降解。
实施例10多肽化合物在大鼠体内的药代动力学性质
大鼠给予50nmol/kg的皮下(s.c.)注射给药,在给药后0.25,0.5,1,2, 4,8,16,24,36和48小时收集血样。使用乙腈沉淀蛋白质后,用LC-MS分析血浆样品。用WinonLin5.2.1(非房室模型)计算药代参数和半衰期(表4)。
表4:多肽化合物在大鼠体内的药代动力学概貌
样品 | T1/2(h) | Cmax(ng/mL) |
ZP3022 | 1.1 | 435 |
Liraglutide | 4.3 | 419 |
Semaglutide | 9.1 | 474 |
SEQ ID NO:5 | 5.8 | 529 |
SEQ ID NO:6 | 12.2 | 592 |
如表4结果显示,本发明的多肽化合物的体内半衰期显著延长,分别优于一天一次给药的liraglutide和一周一次给药的semaglutide,并且半衰期显著优于 ZP3022,具有支持每天一次和每周一次给药的药代动力学特征。
实施例11多肽化合物对饮食诱导肥胖(DIO)小鼠血糖、体重和血脂的影响
雄性C57BL/6J小鼠,体重22g左右,模型组共42只,用Research Diets公司的D12492高脂饲料饲养18周造DIO小鼠模型。在给药开始前,各组DIO小鼠按照体重随机分组,共分为5组,每组6只,分别为生理盐水组(对照高脂饮食组)、阳性对照组(ZP3022、liraglutide和semaglutide)和受试样品组(SEQ ID NO:5,SEQ ID NO:6)。对照高脂饮食组每天三次皮下注射生理盐水(10 mg/kg),ZP3022(25nmol/kg)每天三次皮下注射,SEQ IDNO:5和liraglutide (剂量都为25nmol/kg)每天两次皮下注射,semaglutide,SEQ ID NO:6(剂量都为25nmol/kg)每两天注射一次,给药周期21天。每天记录小鼠体重变化,实验开始前和结束时使用核磁共振(NMR)来测量体脂量,使用血糖仪测量空腹血糖。在实验结束后,各组小鼠取血,测量血清中甘油三酯和胆固醇含量。
表5:DIO小鼠在3周给药周期内的体重、体脂和空腹血糖变化(%)
样品 | 整体体重变化(%) | 体脂变化(%) | 空腹血糖变化(%) |
对照高脂饮食 | +1.6%(±0.5%) | +2.8%(±1.2%) | +2.9%(±1.0%) |
ZP3022 | -15.1%(±2.3%) | -15.4%(±1.7%) | -17.9%(±2.9%) |
Liraglutide | -16.2%(±3.1%) | -19.9%(±3.6%) | -15.8%(±2.1%) |
Semaglutide | -16.8%(±0.9%) | -20.5%(±1.7%) | -17.9%(±3.7%) |
SEQ ID NO:5 | -28.9%(±1.9%), | -34.9%(±2.9%), | -28.9%(±1.5%), |
SEQ ID NO:6 | -27.1%(±1.4%), | -33.2%(±3.5%), | -27.8%(±2.7%), |
:与对照高脂饮食组相比P<0.001;:与ZP3022、liraglutide和semaglutide 组比P<0.001
如表5结果显示,本发明的多肽化合物的在DIO小鼠体内连续给药3周,可以显著降低小鼠的体重和体脂含量,降低空腹血糖值,并且本发明的多肽化合物的作用显著强于阳性对照药ZP3022、liraglutide和semaglutide。
表6:DIO小鼠在3周给药周期后的血脂数据(以mmol/L表示)
样品 | 甘油三酯 | 胆固醇 |
对照高脂饮食 | 1.31±0.09 | 2.9±0.4 |
ZP3022 | 1.00±0.13 | 1.6±0.3 |
Liraglutide | 1.05±0.07 | 1.7±0.2 |
Semaglutide | 1.04±0.08 | 1.6±0.3 |
SEQ ID NO:5 | 0.77±0.10, | 1.0±0.1, |
SEQ ID NO:6 | 0.79±0.09, | 1.1±0.3, |
:与对照高脂饮食组相比P<0.001;:与ZP3022、liraglutide和semaglutide 组比P<0.01
如表6结果显示,本发明的多肽化合物的在DIO小鼠体内连续给药3周,可以显著降低小鼠的甘油三酯和胆固醇含量,并且本发明的多肽化合物的作用显著强于阳性对照药ZP3022、liraglutide和semaglutide。
实施例12多肽化合物对db/db小鼠糖化血红蛋白(HbA1c)、空腹血糖和胰岛面积的影响
雄性db/db小鼠,随机分组,每组6只。适应性饲养一周后,尾部取血测量治疗开始前初始HbA1c(%)数值和空腹血糖数值。空白组每天三次皮下注射给予生理盐水(10mg/kg),给药组分为4组,分别皮下注射25nmol/kg的ZP3022 (每天三次),semaglutide(每两天一次),liraglutide(每天两次),SEQ ID NO: 5(每天两次),SEQ ID NO:6(每两天一次)。治疗周期为5周,治疗结束后小鼠禁食过夜后测量空腹血糖数值,同时取血测量HbA1c(%)数值。最后小鼠处死,取胰腺做切片,HE染色后在10倍镜下测量各组小鼠的胰岛面积。
表7:db/db小鼠在5周给药周期内的HbA1c和空腹血糖变化(%)
:与对照高脂饮食组相比P<0.001;:与ZP3022、liraglutide和semaglutide 组比P<0.01
如表7结果显示,本发明的多肽化合物的在db/db小鼠体内连续给药5周,可以降低HbA1c和空腹血糖,显著优于阳性对照药ZP3022、liraglutide和 semaglutide,说明具有很好的血糖控制作用。
表8:db/db小鼠在5周给药后的胰岛面积(以μm2表示)
样品(剂量) | 胰岛面积 |
生理盐水 | 21125±1726 |
ZP3022 | 28614±1618 |
Liraglutide | 28918±1348 |
Semaglutide | 29158±1541 |
SEQ ID NO:1 | 37986±2158, |
SEQ ID NO:6 | 36715±1948, |
与生理盐水组相比P<0.001;:与ZP3022、liraglutide和semaglutide组比P <0.001;
如表8结果显示,本发明的多肽化合物的在db/db小鼠体内连续给药5周,可以显著增加db/db小鼠的胰岛面积,说明具有很高的促进胰腺组织的细胞增殖和胰岛再生的作用,并且本发明的多肽化合物的作用显著强于阳性对照药 ZP3022、liraglutide和semaglutide。
实施例13多肽化合物的免疫原性
采用来自50例中国人捐赠者的外周血单个核细胞(PBMC)进行了诱导T 细胞增殖的免疫原性实验。PBMC在AIMV培养基中培养,并添加到24孔板(2 mL)中以达到最终浓度~3×106cells/mL,然后通过在AIMV培养基中添加ZP3022,semaglutide,6a(选自J.Med.Chem.2020,63,12595-12613),SEQ ID NO:5,SEQ ID NO:6来刺激PBMC。24孔板在37℃的二氧化碳培养箱(5%) 中培养8天。第5天、第6天、第7天和第8天,将培养板各孔的细胞转移到 96孔板上。用[3H]-胸腺嘧啶核苷对培养物进行处理,再培养18小时,并测定每个孔的每分钟计数(cpm)。刺激指数(SI)是通过将每个供体的试验孔的增殖反应(cpm)除以培养基处理(cpm)的增殖反应来计算的,大于2.0的SI被视为阳性。通过将整个时间过程(5-8天)内有阳性反应的捐赠者数量占接受测试的捐赠者总数的百分比来计算捐赠者的响应百分比。
如图1结果所示,本发明的多肽化合物的捐赠者反应比例显著低于ZP3022, 6a和semaglutide,说明本发明的多肽化合物具有更低的免疫原性。
虽然本发明已以较佳实施例揭露如上,然其并非用以限定本发明。本发明所属技术领域中具有通常知识者,在不脱离本发明的精神和范围内,当可作各种的更动与润饰。因此,本发明的保护范围当视权利要求书所界定者为准。
Claims (8)
1.一类GLP-1/glucagon/gastrin受体三重激动多肽化合物,其特征在于,所述多肽化合物的氨基酸序列通式为:
His-Xaa1-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Xaa2-Tyr-Xaa3-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Xaa4-Xaa5-Tyr-Gly-Trp-Leu-Asp-Phe-NH2;
其中:
Xaa1取自Aib,Ser或D-Ser;
Xaa2取自Lys或侧链被修饰的Lys;
Xaa3取自Leu、Lys或侧链被修饰的Lys;
Xaa4取自AEEA或不存在;
Xaa5取自AEEA或不存在;
其中,侧链被修饰的Lys是Lys(γ-Glu-CO-(CH2)n-CH3)或Lys(AEEA-AEEA-γ-Glu-CO-(CH2)n-COOH),Lys(γ-Glu-CO-(CH2)n-CH3)的结构式如下式所示:
Lys(AEEA-AEEA-γ-Glu-CO-(CH2)n-COOH)的结构式如下式所示:
其中,n为自然数,且12≤n≤20。
2.根据权利要求1所述的一类GLP-1/glucagon/gastrin受体三重激动多肽化合物,其特征在于,所述n是14、16、18或20。
3.根据权利要求1所述的一类GLP-1/glucagon/gastrin受体三重激动多肽化合物,其特征在于,所述多肽化合物的氨基酸序列是下列序列之一:
(1)
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH2;
(2)
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH2;
(3)
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(γ-Glu-CO-(CH2)14-CH3)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH2;
(4)
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH2;
(5)
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(γ-Glu-CO-(CH2)14-CH3)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH2;
(6)
His-D-Ser-Gln-Gly-Thr-Tyr-Thr-Asn-Asp-Val-Ser-Lys-Tyr-Lys(AEEA-AEEA-γ-Glu-CO-(CH2)16-COOH)-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-AEEA-AEEA-Tyr-Gly-Trp-Leu-Asp-Phe-NH2。
4.权利要求1中所述一类GLP-1/glucagon/gastrin受体三重激动多肽化合物的药学上可接受的盐。
5.根据权利要求4所述的盐,其特征在于,所述盐为GLP-1/glucagon/gastrin受体三重激动多肽化合物与下述化合物中的一种所形成的盐:氢溴酸、盐酸、甲磺酸、磷酸、乙磺酸、甲酸、对甲苯磺酸、乙酸、乙酰乙酸、丙酮酸、果胶酯酸、丁酸、己酸、苯磺酸、庚酸、十一烷酸、苯甲酸、水杨酸、月桂酸、2-(4-羟基苯甲酰基)苯甲酸、肉桂酸、樟脑酸、环戊烷丙酸、3-羟基-2-萘甲酸、樟脑磺酸、二葡糖酸、烟酸、扑酸、丙酸、过硫酸、、苦味酸、3-苯基丙酸、特戊酸、衣康酸、2-羟基乙磺酸、氨基磺酸、十二烷基硫酸、三氟甲磺酸、萘二磺酸、2-萘磺酸、柠檬酸、扁桃酸、抗坏血酸、酒硬脂酸、石酸、草酸、乳酸、琥珀酸、丙二酸、半硫酸、苹果酸、马来酸、藻酸、富马酸、D-葡糖酸、甘油磷酸、葡庚酸、天冬氨酸、硫氰酸或者磺基水杨酸。
6.一种药物组合物,其特征在于,包括权利要求1中所述一类GLP-1/glucagon/gastrin受体三重激动多肽化合物或其药学上可接受的盐及药学上可接受的载体或稀释剂组成。
7.一种药剂,其特征在于,包括权利要求1中所述类GLP-1/glucagon/gastrin受体三重激动多肽化合物或权利要求6中所述药物组合物。
8.权利要求1中所述一类GLP-1/glucagon/gastrin受体三重激动多肽化合物、权利要求4中其药学上可接受的盐、权利要求6中其药物组合物或权利要求7中其药剂在制备用于治疗代谢性疾病或病症的药物中的应用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210823351 | 2022-07-14 | ||
CN2022108233517 | 2022-07-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115819551A true CN115819551A (zh) | 2023-03-21 |
Family
ID=85523946
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211173424.9A Pending CN115819551A (zh) | 2022-07-14 | 2022-09-26 | 一种定点改造的一类glp-1/胰高血糖素/胃泌素受体三重激动剂及其应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115819551A (zh) |
-
2022
- 2022-09-26 CN CN202211173424.9A patent/CN115819551A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112409460B (zh) | 一类glp-1/胰高血糖素受体双重激动剂及其应用 | |
JP6985345B2 (ja) | グルカゴン及びglp−1共アゴニスト化合物 | |
CN106715466B (zh) | 作为选择性胰高血糖素受体激动剂的毒蜥外泌肽-4衍生物 | |
EA038073B1 (ru) | Ацилированное инсулиновое соединение | |
KR102230368B1 (ko) | 아실화 옥신토모듈린 펩타이드 유사체 | |
CN116410297A (zh) | 长效glp-1多肽类似物及其制备方法和应用 | |
CN116143884A (zh) | 一类长效GLP-1/glucagon/GIP受体三重激动剂及其应用 | |
KR20240013798A (ko) | 다중 작용제 및 이의 사용 | |
CN110759991B (zh) | 吉非罗齐-非洲爪蟾胰高血糖素样肽-1衍生物及其应用 | |
CN112759640B (zh) | 一类glp-1/胃泌素受体双重激动剂及其应用 | |
CN112608378B (zh) | 一类glp-1/胆囊收缩素-1受体双重激动剂及其应用 | |
CN114437200A (zh) | 一类glp-1/胃泌素受体双重激动剂及其应用 | |
CN116120425A (zh) | 一种glp-1/gip受体双重激动剂及其应用 | |
WO2021239082A1 (zh) | Glp-1和gip受体双重激动剂化合物及其应用 | |
CN115819551A (zh) | 一种定点改造的一类glp-1/胰高血糖素/胃泌素受体三重激动剂及其应用 | |
CN115461360A (zh) | 持续型glp-1以及胰高血糖素受体双重激动剂 | |
CN116589536B (zh) | 一类长效glp-1/gip受体双重激动剂及其应用 | |
CN115785249B (zh) | 一类glp-1类似物及其应用 | |
CN115960258B (zh) | 一类GLP-1/glucagon/Y2受体三重激动剂及其应用 | |
CN115819619A (zh) | 一类glp-1/y2受体双重激动剂及其应用 | |
CN117186189A (zh) | 一种兼具降糖和减重作用的glp-1/cck-1受体双重激动多肽及其应用 | |
CN117417431A (zh) | 一类对glp-1、胰高血糖素和gip受体具有激动活性的多肽及其应用 | |
CN115873096A (zh) | 一种胰高血糖素糖肽-1和胰高血糖素受体双重激动多肽及其应用 | |
CN117756913A (zh) | 一种新型长效多肽化合物、组合物及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination |