CN1735423A - 胃轻瘫的治疗 - Google Patents
胃轻瘫的治疗 Download PDFInfo
- Publication number
- CN1735423A CN1735423A CNA038080079A CN03808007A CN1735423A CN 1735423 A CN1735423 A CN 1735423A CN A038080079 A CNA038080079 A CN A038080079A CN 03808007 A CN03808007 A CN 03808007A CN 1735423 A CN1735423 A CN 1735423A
- Authority
- CN
- China
- Prior art keywords
- glp
- val
- chemical compound
- glu
- gastroparesis
- 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
- 206010021518 Impaired gastric emptying Diseases 0.000 title claims abstract description 73
- 208000001288 gastroparesis Diseases 0.000 title claims abstract description 62
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class 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 claims abstract description 15
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 155
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 72
- 239000003814 drug Substances 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 37
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 26
- 241001597008 Nomeidae Species 0.000 claims description 19
- 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 claims description 16
- -1 GLP-1 chemical compound Chemical class 0.000 claims description 14
- 101800004266 Glucagon-like peptide 1(7-37) Proteins 0.000 claims description 14
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 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(=O)NCC(O)=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 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 claims description 14
- 108010011459 Exenatide Proteins 0.000 claims description 13
- 206010012601 diabetes mellitus Diseases 0.000 claims description 13
- 229960001519 exenatide Drugs 0.000 claims description 13
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 12
- 239000004474 valine Substances 0.000 claims description 12
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 claims description 11
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 claims description 11
- 239000004471 Glycine Substances 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 10
- 235000013922 glutamic acid Nutrition 0.000 claims description 9
- 239000004220 glutamic acid Substances 0.000 claims description 9
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 8
- 238000010254 subcutaneous injection Methods 0.000 claims description 5
- 239000007929 subcutaneous injection Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 3
- 239000000556 agonist Substances 0.000 claims description 2
- 108010063245 glucagon-like peptide 1 (7-36)amide Proteins 0.000 claims description 2
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 claims 18
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 claims 18
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical group 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 claims 1
- 230000030136 gastric emptying Effects 0.000 abstract description 16
- 150000001875 compounds Chemical class 0.000 description 79
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 28
- 230000000694 effects Effects 0.000 description 26
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 25
- 210000004369 blood Anatomy 0.000 description 24
- 239000008280 blood Substances 0.000 description 24
- 235000013305 food Nutrition 0.000 description 23
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 20
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 20
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 20
- 229940079593 drug Drugs 0.000 description 20
- 210000002784 stomach Anatomy 0.000 description 20
- 150000001413 amino acids Chemical group 0.000 description 18
- 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 18
- 208000024891 symptom Diseases 0.000 description 16
- 235000001014 amino acid Nutrition 0.000 description 14
- 229940024606 amino acid Drugs 0.000 description 14
- 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 12
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 12
- 239000008103 glucose Substances 0.000 description 12
- 230000036470 plasma concentration Effects 0.000 description 12
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 11
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 10
- 210000001035 gastrointestinal tract Anatomy 0.000 description 10
- 102000004877 Insulin Human genes 0.000 description 9
- 108090001061 Insulin Proteins 0.000 description 9
- 229940125396 insulin Drugs 0.000 description 9
- 230000000968 intestinal effect Effects 0.000 description 9
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 8
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 8
- 239000004472 Lysine Substances 0.000 description 8
- 230000002218 hypoglycaemic effect Effects 0.000 description 8
- 235000018977 lysine Nutrition 0.000 description 8
- 235000012054 meals Nutrition 0.000 description 8
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 7
- 230000000857 drug effect Effects 0.000 description 7
- 208000002551 irritable bowel syndrome Diseases 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000012856 packing Methods 0.000 description 7
- 210000004203 pyloric antrum Anatomy 0.000 description 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 6
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 6
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 6
- 239000004473 Threonine Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 230000008602 contraction Effects 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000003203 everyday effect Effects 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 230000007774 longterm Effects 0.000 description 6
- 239000000825 pharmaceutical preparation Substances 0.000 description 6
- 235000004400 serine Nutrition 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 235000008521 threonine Nutrition 0.000 description 6
- 239000004475 Arginine Substances 0.000 description 5
- 208000013016 Hypoglycemia Diseases 0.000 description 5
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 5
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 5
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 5
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 5
- 235000009697 arginine Nutrition 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 5
- 235000014304 histidine Nutrition 0.000 description 5
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 5
- 229960000310 isoleucine Drugs 0.000 description 5
- 229930182817 methionine Natural products 0.000 description 5
- 108090000204 Dipeptidase 1 Proteins 0.000 description 4
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 4
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 4
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 235000004279 alanine Nutrition 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 235000003704 aspartic acid Nutrition 0.000 description 4
- 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 4
- 102000006635 beta-lactamase Human genes 0.000 description 4
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 201000006549 dyspepsia Diseases 0.000 description 4
- 108010015174 exendin 3 Proteins 0.000 description 4
- LMHMJYMCGJNXRS-IOPUOMRJSA-N exendin-3 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(N)=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](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@H](C)O)[C@H](C)O)C(C)C)C1=CC=CC=C1 LMHMJYMCGJNXRS-IOPUOMRJSA-N 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 238000007689 inspection Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000000902 placebo Substances 0.000 description 4
- 229940068196 placebo Drugs 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 210000001187 pylorus Anatomy 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 3
- 108091027981 Response element Proteins 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- DCSUBABJRXZOMT-IRLDBZIGSA-N cisapride Chemical compound C([C@@H]([C@@H](CC1)NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)OC)N1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-IRLDBZIGSA-N 0.000 description 3
- 229960005132 cisapride Drugs 0.000 description 3
- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 description 3
- 229940126534 drug product Drugs 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 3
- 201000001421 hyperglycemia Diseases 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 230000001537 neural effect Effects 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000008673 vomiting Effects 0.000 description 3
- 150000003952 β-lactams Chemical class 0.000 description 3
- 206010000087 Abdominal pain upper Diseases 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- OBMZMSLWNNWEJA-XNCRXQDQSA-N C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 Chemical compound C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 OBMZMSLWNNWEJA-XNCRXQDQSA-N 0.000 description 2
- 101800000224 Glucagon-like peptide 1 Proteins 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
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 101710176384 Peptide 1 Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- 102100040918 Pro-glucagon Human genes 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- INJRKJPEYSAMPD-UHFFFAOYSA-N aluminum;silicic acid;hydrate Chemical compound O.[Al].[Al].O[Si](O)(O)O INJRKJPEYSAMPD-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 239000005441 aurora Substances 0.000 description 2
- 229910052788 barium Inorganic materials 0.000 description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 2
- 230000037058 blood plasma level Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 210000001198 duodenum Anatomy 0.000 description 2
- 229960003276 erythromycin Drugs 0.000 description 2
- 239000002389 essential drug Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 206010016766 flatulence Diseases 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 230000002473 insulinotropic effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229940126701 oral medication Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 230000000291 postprandial effect Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000004206 stomach function Effects 0.000 description 2
- 229910052713 technetium Inorganic materials 0.000 description 2
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 230000001515 vagal effect Effects 0.000 description 2
- 210000001186 vagus nerve Anatomy 0.000 description 2
- MGOGKPMIZGEGOZ-REOHCLBHSA-N (2s)-2-amino-3-hydroxypropanamide Chemical compound OC[C@H](N)C(N)=O MGOGKPMIZGEGOZ-REOHCLBHSA-N 0.000 description 1
- NGJOFQZEYQGZMB-KTKZVXAJSA-N (4S)-5-[[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[2-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-2-oxoethyl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]propanoyl]amino]-5-oxopentanoic acid 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(O)=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=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NGJOFQZEYQGZMB-KTKZVXAJSA-N 0.000 description 1
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- 206010009657 Clostridium difficile colitis Diseases 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-GSVOUGTGSA-N D-glutamine Chemical compound OC(=O)[C@H](N)CCC(N)=O ZDXPYRJPNDTMRX-GSVOUGTGSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 208000027219 Deficiency disease Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 101800004295 Glucagon-like peptide 1(7-36) Proteins 0.000 description 1
- 241000270431 Heloderma suspectum Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- ULEBESPCVWBNIF-BYPYZUCNSA-N L-arginine amide Chemical compound NC(=O)[C@@H](N)CCCNC(N)=N ULEBESPCVWBNIF-BYPYZUCNSA-N 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 206010033109 Ototoxicity Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 208000003100 Pseudomembranous Enterocolitis Diseases 0.000 description 1
- 206010037128 Pseudomembranous colitis Diseases 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000003906 autonomic nervous system functioning Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000005178 buccal mucosa Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000009956 central mechanism Effects 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000018823 dietary intake Nutrition 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000003631 expected effect Effects 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 201000000117 functional diarrhea Diseases 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000007661 gastrointestinal function Effects 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 239000011521 glass Substances 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
- 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
- 230000012447 hatching Effects 0.000 description 1
- 208000024798 heartburn Diseases 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 230000035873 hypermotility Effects 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000030214 innervation Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000003750 lower gastrointestinal tract Anatomy 0.000 description 1
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 239000002398 materia medica Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940100630 metacresol Drugs 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000005497 microtitration Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 231100000262 ototoxicity Toxicity 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229940048914 protamine Drugs 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000008430 psychophysiology Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000036186 satiety Effects 0.000 description 1
- 235000019627 satiety Nutrition 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000701 toxic element Toxicity 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Immunology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Neurosurgery (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Nutrition Science (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Emergency Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明与GLP-1化合物用于治疗胃轻瘫有关。胃轻瘫患者通常经历胃排空延迟。GLP-1化合物通常可以用于调节此类患者的胃排空状况。
Description
本发明涉及将胰高血糖素样多肽(GLP-1)化合物用于治疗胃轻瘫。胃轻瘫,即胃动力不足,是胃肠道(GI)***发生的一种麻痹。这是引起自主神经***功能丧失或异常的一类神经障碍,导致摄入食物后胃排空的延迟。胃由两部分组成。上端称为胃近端或者基底部,是容纳吞下的食物和液体的部位。下端称为胃远端或者胃窦,是食物来回进行搅拌直至成为小碎片的部位,而后胃由此将食物排入十二指肠,即小肠的起始部分。固相食物的排空是由胃窦有力的环形收缩完成的。正常人进食固体食物会导致胃的收缩,即胃窦部开始出现一种贯穿胃窦部的协调的波浪状运动,频率约为每分钟三次。在胃轻瘫患者中,这种电波运动减弱且胃收缩频率降低,有时收缩力的减弱会导致食物滞留在胃中。
胃轻瘫可能使患者表现得非常虚弱。胃轻瘫的症状包括恶心,呕吐,进食早期的饱腹感,腹部胀气,上腹痛,或出现烧心,厌食。胃轻瘫出现在非糖尿病患者身上,但在1型和2型糖尿病患者中也非常常见。大约75%的糖尿病患者会出现不同类型的轻度胃肠功能异常,约有25%到35%的糖尿病患者患有胃轻瘫。糖尿病患者中此病的易患率如此之高的原因尚不清楚;但是因高血糖症导致胃排空延迟及其伴随症状出现恶化时,血糖的控制显得至关重要。
目前的治疗方法并不完全有效,且常出现不良副作用。例如,可以给患者服用促运动的和止吐药治疗胃排空延迟。McCallum,R.等Diabetic and nondiabetic gastroparesis:current treatment options 1Gastroenterology 1-7(1998)。对于因患重症或者有其他原因不能口服用药的患者通常可以静脉注射红霉素进行治疗。然而红霉素会导致胃肠道毒性,耳毒性和假膜性结肠炎,并会诱发产生耐药的细菌菌株。对于可以口服用药的患者而言用西沙比得(cisapride)治疗可能最为有效。西沙比得的副作用包括腹部不适和肠道蠕动频率增加。此外,严重的药物相互作用可以导致心律失常;因此这种药在美国的应用受到了严格的限制。很明显有关这种病的治疗还远未能满足医疗的需求。
如果对糖尿病患者进行严格的胰岛素治疗使他们的血糖得到良好的控制,那么胃轻瘫的严重程度和其伴随症状也会得到一定程度的改善。但是,胃轻瘫及相应的胃排空的延迟增加了用胰岛素或口服降糖药治疗糖尿病患者出现低血糖和高血糖的风险。当因胃轻瘫导致食物不能顺利被运送到小肠时会增加低血糖的风险。正常的餐后血糖升高出现延迟,这使得当血糖水平仍很低时,餐前使用的胰岛素却已达到血浓度的峰值。最终血糖水平在数小时后升高;而这时的胰岛素浓度已经开始下降,这样便没有足够的胰岛素来中和高血糖了。因此,对于伴有中到重度胃轻瘫的糖尿病患者而言,由于不能预测餐后血糖水平的升高时间,要有效地控制其血糖几乎是不可能的。
应用GLP-1化合物治疗胃轻瘫解决了与应用无效的和有严重副作用的药物有关的很多问题。此外,GLP-1具有促胰岛素活性,但不会导致低血糖症:因此,GLP-1不仅可以治疗糖尿病患者的胃轻瘫,而且可以解决很多这类患者在使用胰岛素或者口服药剂治疗时血糖控制不佳的问题。
开发GLP-1的类似物和衍生物主要是用来治疗2型糖尿病。除了已在文献中记录的GLP-1的胰岛素活化作用,这种多肽还有其他一些有趣的生理学作用,包括可以导致大鼠胃排空延迟并抑制小肠的运动。[Imeryuz,N.等Glucagon-like peptide-1 inhibits gastricemptying via vagal afferent-mediated central mechanisms,273 Am.J.Physiol.,G920-G927(1997);Willms,B.等Gastric emptying,glucoseresponses,and insulin secretion after a liquid test meal:Effects ofexogenous glucagons-like peptide-1(GLP-1)-(7-36)Amide in type 2(noninsulin dependent)diabetic patients,81 J.Clin.Endocrinology,327-332(1996);Wettergren,A.等The inhibitory effect of glucagons-like peptide-l(GLP-1)7-36 amide on gastric acid secretion in humansdepends on an intact vagal innervation,40 Gut 597-601(1997);Tolessa,T.等Inhibitory effect of glucagons-like peptide-1 on smallbowel motility.102 J.Clin,Invest.,764-774(1998)。另外,GLP-1已被用于治疗肠易激惹综合征(IBS)和功能性腹泻。参见美国专利6,348,447 B1。
肠易激惹综合征(IBS)和一些类型的功能性消化不良与胃轻瘫有明显的不同。功能性消化不良通常表现为慢性的或者反复发作的腹部中间部位的疼痛。肠易激惹综合征(IBS)会出现结肠的异常收缩,从而影响粪便的推进,并促进与水的混合和吸收。也可出现小肠的运动过强,这种运动导致的小肠间歇性的痉挛是疼痛的主要原因。尽管胃肠运动功能涉及复杂的内部相互作用,这其中的很多机制尚未完全理解,但是显然IBS和一些类型的功能性消化不良与下胃肠道的问题有关,而由胃排空延迟所导致的胃轻瘫则与上胃肠道的问题有关。鉴于已表明GLP-1确实可以导致胃排空延迟和平滑肌收缩抑制,那么这种多肽可以用于治疗因肌肉收缩减弱和胃排空延迟所致的胃轻瘫就令人感到惊讶了。有一项令人兴奋的发现,即GLP-1的促胰岛素活性是葡萄糖依赖性的。与使用胰岛素不同,使用GLP-1没有导致低血糖的风险。因此,包括GLP-1类似物,GLP-1衍生物,和GLP-1受体激动剂在内的GLP-1化合物,均可用于使糖尿病患者血糖正常,同样也可以用于治疗非糖尿病患者的胃轻瘫。
本发明包括对胃轻瘫患者进行治疗的方法和应用GLP-1制备治疗胃轻瘫的药物,上述方法包括:将有效量的GLP-1施用于患者。胃轻瘫患者可以为非糖尿病患者或糖尿病患者。GLP-1化合物可由本领域技术人员通过任何已知的方法给药。优选GLP-1化合物通过皮下注射,口服,或者通过颊部粘膜吸收给药。
图1:图中显示在给予2型糖尿病患者安慰剂(基线)和Val8-GLP-1(7-37)OH一次日用药量为2.5mg(组1),和3.5mg(组2)之后的平均(+/-SEM)血糖浓度曲线。
图2:图中显示在给予2型糖尿病患者安慰剂(基线)和Val8-GLP-1(7-37)OH一次日用药量为4.5mg(组3和4)之后的平均(+/-SEM)血糖浓度曲线。
GLP-1化合物的用药方法和成分对于治疗胃轻瘫是有效的。胃轻瘫与胃排空缺陷有关,是由于胃和幽门收缩不协调所致。GLP-1化合物可以调节胃和/或幽门收缩来减轻或消除胃排空延迟。
有40%的胃轻瘫患者病因不明。但是有大约25%到35%的糖尿病患者患有这种疾病,一项研究发现这种疾病的易患率高达59%。[Soykan,I.等Demography,clinical characteristics,psychological andabuse profile,treatment and long term follow-up of patients withgastroparesis.11 Dig.Dis.Sci.2398-2404(1998);Hiba,R.,Is there adifference in the prevalence of gaslrointeslinal symptoms betweentype1 and type 2 diabetics?4 Gastroenterology A79(1999)].
胃轻瘫的症状包括恶心,呕吐,餐后胀气,上腹痛,厌食症,和早期胞腹感。在更加严重的病例中,患者可以出现在餐后数小时呕吐未消化的食物,并且伴发体重减轻,脱水,和营养不良体征同时可以表现为震水音阳性。胃轻瘫的***性原因可以通过检查患者是否患有糖尿病,甲状腺功能减退症,皮质醇缺乏症,高钙血症和妊娠等情况进行评估。钡餐检查,内窥镜,和上消化道系列检查可以排除消化道溃疡性疾病和胃流出道梗阻。钡从胃中排空不良即提示胃排空减慢。然而胃闪烁扫描摄影术才是正确诊断胃轻瘫的最终标准。在这项检查中,患者需要服用99-M锝(TC)标记的含硫胶体或其他有放射性标记配体的食物。然后使用一种γ-照像机测量胃所在区域的放射性。因为液体的食物不能反应实际的胃排空情况,所以患者在检查时要服用固体食物。食物排空50%的时间或者特定时间间隔排空食物的百分比即为报告的检测结果。[Thomforde,G.M.等,Evaluation of an inexpensive screening scintigraphic test of gastricemptying,36 J.Nucl.Med.93(1995)].用C13标记的食物进行呼气试验也可检测胃排空。C13会在到达小肠时被吸收,在呼出的气体中检测到的C13可以显示胃的排空情况。[Ghoos,Y.S.等,104Gastroenterology 1640-1647(1993)]。胃电描记法(EGG)与心电图类似,是通过皮肤电极测量生物电活性,这种检查也可用于诊断胃轻瘫。[Stem,R.N.等EGG;Common issues in validation and methodology,24 Psychophysiology 55-64(1987)].
在胃功能正常的情况下,当固体食物到达胃时,胃底部松弛以容纳摄入的食物。胃的收缩可以混合并研磨胃窦中的食物。胃窦的收缩可以混合并搅拌食物颗粒,直至食物的大小小于3mm,这一过程需要30到40分钟(滞留阶段)。幽门收缩与胃窦收缩相协调,推进食物颗粒进入十二指肠。这种协调过程的复杂顺序是由来自脑和脊髓的外来神经所构成的位于胃壁和肠壁上的复杂的神经网络控制的,这些神经网络在局部释放诸如胺和多肽这样的神经递质,并通过它们改变胃平滑肌细胞的兴奋性。这些神经网络的任何部分出现异常都会导致胃排空障碍和胃轻瘫。
因为过去所给出的多数文献证明给人服用天然的GLP-1时会出现胃排空延迟,所以GLP-1化合物治疗胃轻瘫的功能是令人惊讶的。[参见Willms,B.,等Gastric emptying,glucose responses,andinsulin secretion after a liquid test meal:effects of exogenousglucagons-likepeptide(GLP-1)-(7-36)amide in type 2(noninsulindependent)diabetic patients,81 J.Clin.Endocrinology Metabolism,327-332(1996)]。图1和图2中所描述的研究表明,与安慰剂组相比,给没有胃轻瘫症状的2型糖尿病患者服用GLP-1化合物不会导致胃排空延迟。每个实验组和对照组在进食固体食物后血糖到达峰值的时间是相同的。GLP-1化合物不会使胃排空延迟,相反可使胃排空正常化,这样患者便不再会出现与胃轻瘫相关的一种或多种症状。
现已有观点认为一氧化氮(NO)是一种神经递质,其也会影响胃和幽门的功能。进一步的动物实验表明,在伴有胃肠道疾患的糖尿病患者体内,负责生成一氧化氮的神经元一氧化氮合成酶(nNOS)的调控失衡。[Watkins等Insulin restores neuronal nitric oxide synthaseexpression and function that is lost in diabetic gastropalhy,106 J.Clin.Invest.373-384(2000)]。神经元一氧化氮合成酶(nNOS)的分子机制尚未被阐明。但在治疗胃轻瘫时,GLP-1化合物间接调节了一氧化氮(NO)的合成。此外,在迷走神经切断术后的患者中GLP-1对胃肠道的一些影响消失了,因此认为GLP-1是通过神经通路发挥作用的。这种通路包括与迷走神经传入神经,中枢神经部分或在迷走神经传出神经内传导相关的GLP-1受体。另外,已证实胃肠道中有GLP-1受体,主要存在于胃和小肠。
尽管可以使用GLP-1化合物治疗没有糖尿病的胃轻瘫患者,但是这种化合物更适合治疗伴有糖尿病的胃轻瘫患者。GLP-1化合物可以通过增加胰岛素的分泌并增强机体对胰岛素的敏感性调节血糖的水平,且不会导致低血糖。因此,GLP-1化合物能够更有效地使伴有胃轻瘫的糖尿病患者的血糖水平正常化,因为这种化合物不仅能够调节这些患者的胃排空,还可以调节任何与胃轻瘫有关的不可预知的胃排空延迟,同时还不会增加患者出现低血糖的风险,因为这种化合物不会导致低血糖。
适用于本发明的GLP-1化合物包括天然GLP-1,GLP-1类似物,GLP-1衍生物,Exendin-4,Exendin-4类似物,Exendin-4衍生物和其他GLP-1受体的激动剂。
本发明中所涵盖的GLP-1的类似物与GLP-1(7-37)OH或GLP-1(7-37)OH的片段高度同源,因此这类化合物完全可以与GLP-1受体相结合,并起始信号传导通路,最终使与胃轻瘫相关的一种或多种症状得以改善。我们可以用一种体外信号检测法确定GLP-1化合物是否适用于本发明的方法。实例3给出了一个表格,列出了一些GLP-1类似物在体外通过检测GLP-1受体信号分析显示出的活性。可以明确的是,如果GLP-1化合物与GLP-1受体有效结合,便会激活第二信使cAMP。被诱导产生的cAMP水平的范围可以用能够激发一种诸如荧光素酶或β-内酰胺酶这样的报告基因表达的cAMP反应元件进行测定。
可以用这种分析方法测定EC50的药效,即在一次单独的剂量反应试验中GLP-1化合物在发挥50%活性时的有效浓度。这种检测方法使用的是HEK-293 Aurora CRE-BLAM细胞,其可以稳定地表达人的GLP-1受体。这些HEK-293细胞已被稳定地整合入一种含有能激发β-内酰胺酶(BLAM)基因表达的cAMP反应元件(CRE)的DNA载体中。GLP-1类似物与GLP-1受体的相互作用会激发一种信号,这种信号会激活cAMP反应元件,而后促使β-内酰胺酶表达。将经β-内酰胺酶裂解而发出荧光的β-内酰胺酶(Aurora生物科学公司)的CCF2/AM底物加入到已暴露于一定剂量GLP-1激动剂的细胞中,由此测量GLP-1激动剂的效力。Ziokamik等人对该方法做进一步地描述。Ziokamik,等(1998)Science 279:84-88(也可参见实例3)。
优选本发明的GLP-1化合物的体外活性仅比Val8-GLP-1(7-37)OH的体外活性最多低十倍,优选GLP-1化合物的体外活性仅比Val8-GLP-1(7-37)OH体外活性最多低五倍,更优选GLP-1化合物的体外活性仅比Val8-GLP-1(7-37)OH体外活性最多低三倍。最优选GLP-1化合物的体外活性不比Val8-GLP-1(7-37)OH的体外活性低。
天然GLP-1的生物活性形式是由两个截短肽段GLP-1(7-37)OH和GLP-1(7-36)酰胺组成。通式1列出了这两个自然存在的截短的GLP-1肽段,SEQ ID NO:1:
7 8 9 10 11 12 13 14 15 16 17
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-
18 19 20 21 22 23 24 25 26 27 28
Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-
29 30 31 32 33 34 35 36 37
Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Xaa
通式1,SEQ ID NO:1,其中:
37位的Xaa是Gly,或-NH2。
优选的GLP-1化合物的氨基酸序列与SEQ ID NO:1中的序列相同,或其中的一,二,三,四或五个氨基酸与序列1不同。
本领域已知的GLP-1化合物1,如GLP-1(7-34)和GLP-1(7-35),GLP-1(7-36),Gln9-GLP-1(7-37),D-Gln9-GLP-1(7-37),Thr16-Lys18-GLP-1(7-37)和Lys18-GLP-1(7-37)。像GLP-1(7-34)和GLP-1(7-35)这样的GLP-1化合物已在美国专利5,118,666号中公开。其他已知有生物活性的GLP-1类似物已在美国专利第5,977,071;5,545,618;5,705,483;5,977,071;6,133,235号中公开。Adelhorst,等,J.Biol.Chem.269:6275(1994);和Xiao,Q.,等(2001),Biochemistry40:2860-2869。
GLP-1化合物也包括在GLP-1(7-37)OH,N末端和/或C末端添加一个或多个氨基酸所形成的多肽或其片段或类似物。优选是在GLP-1(7-37)OH的C末端加一个至八个氨基酸。优选这种类型的GLP-1化合物可以有约39个氨基酸。“经延伸的”GLP-1化合物中与GLP-1(7-37)OH相对应的氨基酸用相同的编号指示出来。例如通过向GLP-1(7-37)OH的N末端增加两个氨基酸得来的GLP-1化合物的N末端氨基酸是第5位;通过向GLP-1(7-37)OH的C末端增加一个氨基酸得来的GLP-1化合物的C末端氨基酸是第38位。延伸的GLP-1化合物的38-45位氨基酸与Exendin-3或Exendin-4相应位置的氨基酸相同或仅为保守替换。Exendin-3或Exendin-4的氨基酸序列列于通式II中,SEQ ID NO:2。
SEQ ID NO:2
7 8 9 10 11 12 13 14 15 16 17
His-Xaa-Xaa-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-
18 19 20 21 22 23 24 25 26 27 28
Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-
29 30 31 32 33 34 35 36 37 38 39
Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-
40 41 42 43 44 45
Gly-Ala-Pro-Pro-Pro-Ser
其中:
第8位的Xaa为Ser或Gly;且
第9位的Xaa为Asp或Glu;
第45位的Ser为Ser或Ser-NH2。
Exendin-3的第八位为Ser,第九位为Asp。Exendin-4的第八位为Gly,第九位为Glu。
最优选的GLP-1化合物包括GLP-1的类似物,其类似物或片段的主链的第八位(第八位类似物)都有一个非丙氨酸的氨基酸。第八位优选的氨基酸为甘氨酸,缬氨酸,亮氨酸,异亮氨酸,丝氨酸,苏氨酸或甲硫氨酸,其中更优选缬氨酸或甘氨酸。
另外的优选的GLP-1化合物是除了第八位和第二十二位以外与GLP-1(7-37)OH序列相同的GLP-1类似物,其中第八位优选为甘氨酸,缬氨酸,亮氨酸,异亮氨酸,丝氨酸,苏氨酸或甲硫氨酸,其中更优选甘氨酸或缬氨酸,第二十二位为谷氨酸,赖氨酸,天冬氨酸或精氨酸,其中更优选谷氨酸或赖氨酸。
其它优选的GLP-1化合物是除了第八位和第三十位以外与GLP-1(7-37)OH序列相同的GLP-1类似物,其中第八位优选为甘氨酸,缬氨酸,亮氨酸,异亮氨酸,丝氨酸,苏氨酸或甲硫氨酸,其中更优选缬氨酸或甘氨酸,第三十位为谷氨酸,天冬氨酸,丝氨酸或组氨酸,其中更优选谷氨酸。
其它优选的GLP-1化合物是除了第八位和第三十七位以外与GLP-1(7-37)OH序列相同的GLP-1类似物,其中第八位优选为甘氨酸,缬氨酸,亮氨酸,异亮氨酸,丝氨酸,苏氨酸或甲硫氨酸,其中更优选的为缬氨酸或甘氨酸,第三十七位为组氨酸,赖氨酸,精氨酸,苏氨酸,谷氨酸,天冬氨酸,色氨酸,酪氨酸,苯丙氨酸,其中更优选的为组氨酸。
其它优选的GLP-1化合物是除了第八位,第二十二位和第二十七位以外与GLP-1(7-37)OH序列相同的GLP-1类似物,其中第八位优选为甘氨酸,缬氨酸,亮氨酸,异亮氨酸,丝氨酸,苏氨酸或甲硫氨酸,其中更优选缬氨酸或甘氨酸,第二十二位为谷氨酸,赖氨酸或精氨酸,其中更优选为谷氨酸或赖氨酸,第二十七位为丙氨酸,赖氨酸,精氨酸,色氨酸,酪氨酸,苯丙氨酸或组氨酸,其中更优选为丙氨酸。
在用于描述GLP-1化合物的命名方法中,我们在化合物的母药物名称前面注明了取代氨基酸及其位置。例如Val8-GLP-1(7-37)OH就是指GLP-1(7-37)OH(通式I,SEQ ID NO:1)中正常的第八位的丙氨酸被缬氨酸所取代的一种GLP-1化合物。
其他适合的GLP-1化合物包括:
Val8-GLP-1(7-37)OH, Gly8-GLP-1(7-37)OH,Glu22-GLP-1(7-37)OH,Asp22-GLP-1(7-37)OH,Arg22-GLP-1(7-37)OH,Lys22-GLP-1(7-37)OH,Cys22-GLP-1(7-37)OH,Val8-Glu22-GLP-1(7-37)OH,Val8-Asp22-GLP-1(7-37)OH,Val8-Arg22-GLP-1(7-37)OH,Val8-Lys22-GLP-1(7-37)OH,Val8-Cys22-GLP-1(7-37)OH,Gly8-GIu22-GLP-1(7-37)OH,Gly8-Asp22-GLP-1(7-37)OH,Gly8-Arg22-GLP-1(7-37)OH,Gly8-Lys22-GLP-1(7-37)OH,Gly8-Cya22-GLP-1(7-37)OH,Glu22-GLP-1(7-36)NH2,Asp22-GLP-1(7-36)NH2,Arg22-GLP-1(7-36)NH2,Lys22-GLP-1(7-36)NH2,Cys22-GLP-1(7-36)NH2,Val8-Glu22-GLP-1(7-36)NH2,Val8-Asp22-GLP-1(7-36)NH2,Val8-Arg22-GLP-1(7-36)NH2,Val8-Lys22-GLP-1(7-36)NH2,Val8-Cys22-GLP-1(7-36)NH2,Gly8-Glu22-GLP-1(7-36)NH2,Gly8-Asp22-GLP-1(7-36)NH2,Gly8-Arg22-GLP-1(7-36)NH2,Gly8-Lys22-GLP-1(7-36)NH2,Gly8-Cys22-GLP-1(7-36)NH2,Lys23-GLP-1(7-37)OH,Val8-Lys23-GLP-1(7-37)OH,Gly8-Lys23-GLP-1(7-37)OH,His24-GLP-1(7-37)OH,Val8-His24-GLP-1(7-37)OH,Gly8-His24-GLP-1(7-37)OH,Lys24-GLP-1(7-37)OH,Val8-Lys24-GLP-1(7-37)OH,Gly8-Lys24-GLP-1(7-37)OH,Glu30-GLP-1(7-37)OH,Val8-Glu30-GLP-1(7-37)OH,Gly8-Glu30-GLP-1(7-37)OH,Asp30-GLP-1(7-37)OH,Val8-Asp30-GLP-1(7-37)OH,Gly8-Asp30-GLP-1(7-37)OH,Gln30-GLP-1(7-37)OH,Val8-Gln30-GLP-1(7-37)OH,Gly8-Gln30-GLP-1(7-37)OH,Tyr30-GLP-1(7-37)OH,Val8-Tyr30-GLP-1(7-37)OH,Gly8-Tyr30-GLP-1(7-37)OH,Ser30-GLP-1(7-37)OH,Val8-Ser30-GLP-1(7-37)OH,Gly8-Ser30-GLP-1(7-37)OH,His30-GLP-1(7-37)OH,Val8-His30-GLP-1(7-37)OH,Gly8-His30-GLP-1(7-37)OH,Glu34-GLP-1(7-37)OH,Va18-Glu34-GLP-1(7-37)O-H,Gly8-Glu34-GLP-1(7-37)OH,Ala34-GLP-1(7-37)OH,Val8-Ala34-GLP-1(7-37)OH,Gly8-Ala34-GLP-1(7-37)OH,Gly34-GLP-1(7-37)OH,Val8-Gly34-GLP-1(7-37)OH,Gly8-Gly34-GLP-1(7-37)OH,Ala35-GLP-1(7-37)OH,Val8-Ala35-GLP-1(7-37)OH,Gly8-Ala35-GLP-(7-37)OH,Lys35-GLP-1(7-37)OH,Val8-Lys35-GLP-1(7-37)OH,Gly8-Lys35-GLP-1(7-37)OH,His35-GLP-1(7-37)OH,Val8-His35-GLP-1(7-37)OH,Gly8-His35-GLP-1(7-37)OH,Pro35-GLP-1(7-37)OH,Val8-Pro35-GLP-1(7-37)OH,Gly8-Pro35-GLP-1(7-37)OH,Glu35-GLP-1(7-37)OH,Val8-Glu35-GLP-1(7-37)OH,Gly8-Glu35-GLP-1(7-37)OH,Val8-Ala27-GLP-1(7-37)OH,Val8-His37-GLP-1(7-37)OH,Val8-Glu22-Lys23-GLP-1(7-37)OH, Val8-Glu22-Glu23-GLP-1(7-37)OH,Val8-Glu22-Ala27-GLP-1(7-37)OH,Val8-Gly34-Lys35-GLP-1(7-37)OH,Val8-His37-GLP-1(7-37)OH,andGly8-His37-GLP-1(7-37)OH.
更优选的GLP-1化合物为:
Val8-GLP-1(7-37)OH,Gly8-GLP-1(7-37)OH,Glu22-GLP-1(7-37)OH,Lys22-GLP-1(7-37)OH,Val8-Glu22-GLP-1(7-37)OH,Val8-Lys22-GLP-1(7-37)OH,Gly8-Glu22-GLP-1(7-37)OH,Gly8-Lys22-GLP-1(7-37)OH,Glu22-GLP-1(7-36)NH2,Lys22-GLP-1(7-36)NH2,Val8-Glu22-GLP-1(7-36)NH2,Val8-Lys22-GLP-1(7-36)NH2,Gly8-Glu22-GLP-1(7-36)NH2,Gly8-Lys22-GLP-1(7-36)NH2,Val8-His37-GLP-1(7-37)OH,Gly8-His37-GLP-1(7-37)OH,Arg34-GLP-1(7-36)NH2,and Arg34-GLP-1(7-37)OH.
其他优选的GLP-1化合物包括:
Val8-Tyr12-GLP-1(7-37)OH,Val8-Tyr12-GLP-1(7-36)NH2,Val8-Trp12-GLP-1(7-37)OH,Val8-Leu16-GLP-1(7-37)OH,Val8-Tyr16-GLP-1(7-37)OH,Gly8-Glu22-GLP-1(7-37)OH,Val8-Leu25-GLP-1(7-37)OH,Val8-Glu30-GLP-1(7-37)OH,Val8-His37-GLP-1(7-37)OH,Val8-Tyr12-Tyr16-GLP-1(7-37)OH,Val8-Trp12-Glu22-GLP-l(7-37)OH,Val8-Tyr12-Glu22-GLP-1(7-37)OH,Val8-Tyr16-Phe19-GLP-1(7-37)OH,Val8-Tyr16-Glu22-GLP-1(7-37)OH,Val8-Trp16-Glu22-GLP-1(7-37)OH,Val8-Leu16-Glu22-GLP-1(7-37)OH,Val8-Ile16-Glu22-GLP-1(7-37)OH,Val8-Phe16-Glu22-GLP-1(7-37)OH,Val8-Trp18-Glu22-GLP-1(7-37)OH,Val8-Tyr18-Glu22-GLP-1(7-37)OH,Val8-Phe18-Glu22-GLP-1(7-37)OH,Val8-Ile18-Glu22-GLP-1(7-37)OH,Val8-Lys18-Glu22-GLP-1(7-37)OH,Val8-Trp19-Glu22-GLP-1(7-37)OH,Val8-Phe19-Glu22-GLP-1(7-37)OH,Val8-Phe20-Glu22-GLP-1(7-37)OH,Val8-Glu22-Leu25-GLP-1(7-37)OH,Val8-Glu22-Ile25-GLP-1(7-37)OH,Val8-Glu22-Val25-GLP-1(7-37)OH,Val8-Glu22-Ile27-GLP-1(7-37)OH,Val8-Glu22-Ala27-GLP-1(7-37)OH,Val8-Glu22-Ile33-GLP-1(7-37)OH,Val8-Glu22-His37-GLP-1(7-37)OH,Val8-Asp9-Ile33-Tyr16-Glu22-GLP-1(7-37)OH,Val8-Tyr16-Trp19-Glu22-GLP-1(7-37)OH,Val8-Trp16-Glu22-Val25-Ile33-GLP-1(7-37)OH,Val8-Trp16-Glu22-Ile33-GLP-1(7-37)OH,Val8-Glu22-Val25-Ile33-GLP-1(7-37)OH,and Val8-Trp16-Glu22-Val25-GLP-1(7-37)OH.
GLP-1化合物也包括“GLP-1衍生物”,即在天然的GLP-1,Exendin-4,或GLP-1或Exendin-4类似物的氨基酸分子的基础上有一个或多个氨基酸侧链,α-碳原子,氨基末端基团,羧基末端基团中有化学修饰的化合物。这种化学修饰包括但不限于增加化学成分,生成新键以及减少化学成分。
在氨基酸侧链基团的修饰包括但不限于赖氨酸ε氨基的乙酰化,精氨酸,组氨酸或赖氨酸N端的烷基化,谷氨酸或天冬氨酸羧基端的烷基化,谷氨酰胺或天冬酰胺的脱酰胺化,但不仅限于此。
末端氨基基团的修饰包括但不限于去氨基,N末端低碳烷基化,N末端双低碳烷基化和N末端的酰基化修饰。末端羧基基团的修饰包括但不限于酰胺、低级烷基酰胺,双烷基酰胺和低级烷基脂修饰。此外,一个或多个侧链基团或末端基团可以由普通的蛋白质化学领域的普通技术人员所了解的保护基团保护起来。氨基酸的α-碳原子可以是单或双甲基化的。
优选的GLP-1衍生物是通过酰化作用合成的。利用脂肪酸的衍生原理,通过促进与血和外周组织中白蛋白上脂肪酸残基结合部位的相互作用所致的GLP-1与血浆白蛋白的结合,延长GLP-1的作用时间。优选的GLP-1衍生物为Arg34-Lys36-(N-ε-(γ-Glu(N-α-十六烷酰基)))-GLP-1(7-37)。GLP-1衍生物和制备这类GLP-1衍生物的方法已由Knudsen等公开(Knudsen等(2000)J.Med.Chem.43:1664-1669)。另外,在很多已公开的申请中都描述了GLP-1的衍生物,GLP-1类似物,Exendin-4和Exendin-4的类似物。参见美国专利第5,512,540号,第6,268,343,WO96/29342,WO98/08871,WO99/43341,WO99/43708,WO99/43707,WO99/43706和WO99/43705号专利。
受保护不被内源性的二肽基肽酶IV(DPP-IV)降解的GLP-1化合物是最优选的。DPP-IV在天然截短的GLP-1N末端的组氨酸残基后剪切,使GLP-1分子失活。由于DPP-IV快速的致失活作用,天然GLP-1的半衰期约为5-10分钟。将GLP-1化合物在人血浆中孵育可以使GLP-1化合物抵抗DPP-IV的降解作用。例如将人血浆与300pmol的GLP-1化合物溶液在37℃孵育六小时。之后按照Deacon等人Deacon等807.CVi′n.Endocrinol.Metab.952-957(1995)的做法,将该溶液进行反相HPLC和放射免疫学测定。第八位GLP-1类似物对DPP-IV的活性有抵抗作用,GLP衍生物如酰基化GLP-1类似物,由于其有大量的酰基基团,可以保护这些类似物的N末端不与DPP-IV发生结合。
许多已知的方法均可生产GLP-1化合物,例如固相合成化学法,从天然原材料中纯化GLP-1分子,重组DNA技术,或将这些方法结合起来。例如,在美国专利第5,118,666;5,120,712;5,512,549;5,977,071和第6,191,102号专利中所描述的制备GLP-1化合物的方法。
本发明的GLP-1化合物可以制备成药学上可接受的组合物。“药学上可接受的”表示这种成份可施用于人。一种药学上可接受的制剂不包含毒性元素,不利的污染等,且不对其中活性物质的活性作用发生干扰。本发明中药学上可接受的成分可制成多种形式,例如粉末,颗粒,片剂,糖衣片,胶囊,糖浆,栓剂,可注射用的溶液,吸入用的制剂,鼻饲用制剂或口腔用的制剂。根据包括GLP-1化合物的组合物的药学上可接受的形式,其可通过多种途径用药,例如口服,鼻饲,吸入或胃肠道外给药。胃肠道外用药包括全身用药,例如肌肉内注射,静脉内注射,皮下注射或腹膜内注射。[参见Gutniak等GLP-1 tablet in type 2 diabetes in fasting and postprandialconditions,20 Diabetes Care 1874-1879(1997);Gutniak,等Potentialtherapeutic levels of glucagon-like peptide 1 achieved in humans by abuccal tablet,19 Diabetes Care 843-848(1996)]。
药学上可接受的药物产品可以包括GLP-1化合物和与药学上可接受的缓冲液结合,该缓冲液的pH值应适用于胃肠道外用药,并调整溶液的稳定性和溶解度的特性。也可向其中添加药学上可接受的抗微生物制剂。间甲酚和酚都是优选的抗微生物制剂。也可向溶液中添加一种或多种药学上可接受的盐,以调整溶液的离子强度或渗透压。还可以添加一种或多种赋形剂,以进一步调整配方的等渗性。甘油就是一种能调整等渗性的赋形剂。
GLP-1化合物的使用可以分为基本用药或长期用药。基本用药是指短期的或按需用药。例如在不伴有糖尿病的胃轻瘫患者中更优选用药方法是相对短期地在餐前或餐后立即使用GLP-1化合物以减轻或缓解与胃轻瘫相关的症状。另外,胃轻瘫及其相关症状可以在特定的几天中加重,或者疾病的严重程度和相关症状会日复一日,周复一周,月复一月地变化。因此,患者可以根据需要服用GLP-1化合物,例如仅在感觉有不适症状时服用。
对伴有胃轻瘫的糖尿病患者,则优选长期服用GLP-1化合物。“长期”通常是指在较长的一个时期内规律用药,每天不超过四次,优选每天不超过两至三次,最优选每天不超过一次。而这里所使用的长期用药的方法可以包括除每天用药之外的其他用药方法。例如,长期用药可采用持续用药模式,这样可以在一个规律药物浓度基础上提供足够的治疗血浆浓度。这样的治疗方式还包括每周用药一次,每月用药一次,甚至是更低频率的用药。
对长期用药而言,更优选的方法是衍生或构建GLP-1化合物以延长GLP-1化合物的作用时间。例如,第8位有改变的GLP-1类似物可以抵抗DPP-IV的裂解作用,从而可以延长药物的作用持续时间。另外,酰基化的GLP-1衍生物有与白蛋白结合的特性,其可以表现出一种延长作用时间的作用模式。GLP-1类似物可以与锌和/或鱼精蛋白相结合,从而可以达到悬浮状态,使药物作用时间延长。例如,参见第WO99/30731,其中有关于GLP-1化合物结晶状态的描述。
GLP-1化合物的“有效量”是在给用药主体服药后能够产生预期疗效,而不会导致无法预期的副作用的剂量。预期的疗效包括与胃轻瘫有关的症状的改善。特别是胃排空变得规律,胃轻瘫缓解。对长期用药而言,要在副作用最小的同时达到预期的疗效,在一个疗程期间,一旦GLP-1化合物的血浆浓度达到一个稳定的状态后便不会明显地波动。如果在一个疗程的治疗中,用药剂量能够维持在本申请中所描述的稳定的范围内,那么药物的血浆浓度不会出现明显的波动。GLP-1化合物在疗效上接近Val8-GLP-1(7-37)OH的两倍以内是优选,此时的血浆浓度约维持在30皮摩尔至200皮摩尔之间,在疗程中血药浓度一旦达到稳定的状态,则血浆浓度优选维持在60皮摩尔至150皮摩尔之间。
Val8-GLP-1(7-37)OH和与之药效相似的GLP-1化合物的最佳血药浓度范围也同样适用于其他有着不同药效的GLP-1化合物,包括Exendin-3和Exendin-4。有着相似药效的GLP-1化合物包括用实例3中所描述的体外检测方法测定的药物活性达到Val8-GLP-1(7-37)OH两倍的之内的药物。
Exendin-4的药效约比Val8-GLP-1(7-37)OH高五倍;因此Exendin-4理想的血浆浓度比理想的Val8-GLP-1(7-37)OH的浓度水平低五倍,这两种化合物具有相近的疗效。这与约6皮摩尔至约40皮摩尔之间的血浆浓度范围是相对应的,这个范围优选是约12皮摩尔至约30皮摩尔之间。另一个GLP-1化合物药效较强的实例是Val8-Glu22-GLP-1(7-37)OH,其药效比Val8-GLP-1(7-37)OH高约三倍。因此,其理想的血浆浓度水平约比已被确定的Val8-GLP-1(7-37)OH浓度低三倍左右。
这项发明还包括人用药物制品,其包括一个装药用的存储容器;包括一定量GLP-1化合物,如GLP-1类似物或衍生物的剂量形式和一个写有能够减轻与胃轻瘫相关的症状或起到治疗胃轻瘫效果的相应用药剂量的包装插页。
“容器”是指任何密闭的,适用于存储,运输,配制和/或处理药物产品的容器。
“包装”是指一种对用户有亲和力的,使用药更方便的设备和/或方便于运输,教育和/或用药的辅助策略。包装可以促进患者服用GLP-1化合物,减少或改善针对患者的教育指导时间,并提供了一个健康经济实用的学习平台,和/或限制了发行渠道的工作负荷。同时,包装可以包括纸包装,但不仅限于此,热缩塑料包顶部透明包装,试验用的赠品,教育性的资料,辅助的补给和/或运输设备。
“包装插页”是指产品的伴随信息,其能向医生,药剂师和患者提供如何用药以及用药的安全性和有效性数据等有关产品的使用信息,和/或患者教育信息。包装插页通常被认为是要用产品的“标签”。
本发明还包括人用药物制品,包括一个包装插页和一个容器,其中所述包装插页描述了治疗胃轻瘫的用药方法和用药剂量。对胃轻瘫的有效治疗包括缓解或消除一种或几种与胃轻瘫有关的症状或者消除所有与胃轻瘫有关的症状。对胃轻瘫的有效治疗还包括胃功能的正常化,包括进食后胃正常排空。
本发明的药物制品中所用的容器就是制药产业中常规应用的。通常所用的容器是一个玻璃制的有盖的密封小药瓶或药筒,还包括有垫圈,隔膜和/或其他适合患者和药剂师使用的配件。另外,容器可以是装有干燥剂的试剂盒的一部分,在吸入注射器之前要进行适当的稀释。其他可选择的容器包括由两个腔室构成的能够将稀释液和干燥的粉末分别装起来的药筒,需要的时候再将其重新混合。在重新混合的时候,有两个腔的药筒可以使稀释液流入装有干燥的粉末的腔室中。优选地容器容积为0.1至100mL,更优选0.5至25mL,更优选5至10mL,最优选容积为1.5至3mL。容器还可以是泡罩包装,胶囊,或泡罩板。其他可供选择的容器包括皮肤用的药膏包装,可植入体内的装置,微球载体和其它储存运输体系包装。
插页可以向医师提供几种剂量选择,不同的剂量产生不同的GLP-1化合物血浆浓度。这里描述了较好的血浆浓度范围。插页最好向医师说明一个用药剂量,患者在以这个剂量服用时GLP-1化合物的血浆浓度就在这里所描述的浓度范围之内。
包装插页给出了一份如何给患者服用一种药品产品的说明,并说明了必要的安全性和有效性信息,使医师,药剂师和患者能够了解有关药品使用的情况。包装插页通常被看作是药物产品的标签。
包装插页可以提供下列适应症或标示说明的部分或所有信息:a)该药适用于胃轻瘫的患者;b)该药适用于伴有糖尿病的胃轻瘫患者;c)该药可改善伴有胃轻瘫的糖尿病患者的血糖控制情况;且d)在缓解或减轻与胃轻瘫相关的一种或多种症状的严重程度的同时不会导致有症状的低血糖。
实例1-在2型糖尿病患者中进行的临床研究:
共有四个实验组,每组有八名2型糖尿病患者长期服用Val8-GLP-1(7-37)OH治疗。前三组患者的用药剂量分别为2.5或3.5或4.5mg,每天皮下注射一次,共注射六天。第四组患者接受的用药剂量为4.5mg,每天皮下注射一次,共注射二十一天。在研究开始前一天,每一位患者都要注射生理盐水作为安慰剂对照。注射药物后要监测血糖13个小时。在研究期间患者所有的用餐都要严格标准化。患者都是门诊病人,仅在第6天和第21天因要进行评估而在医院停留超过24小时。在第1天注射之后,要在四个小时中采集用于检测血糖和Val8-GLP-1(7-37)OH血浆水平的血样。患者都是在每天早晨用药。在用药的第6天(第四组则为第21天)要在用药后26小时采集用于检测血糖和测定Val8-GLP-1(7-37)OH血浆浓度的血样。图1和图2显示了血糖的水平。
实例2-Val8-GLP-1(7-37)OH血浆水平的鉴定::
由于血中会出现内源性的天然GLP-1多肽,和像GLP-1(9-37)OH这类的DPP-TV降解产品,因此可以用酶联免疫吸附试验(ELISA)测定准确的Val8-GLP-1(7-37)OH浓度该方法中未被降解的全长Val8-GLP-1(7-37)OH会被特异性地识别。由于Val8-GLP-1(7-37)OH有免疫反应特性,因此可以被血浆中抗Val8-GLP-1(7-37)OHN末端的特异性抗血清俘获,并固定在微量滴定板上。这种抗血清对Val8-GLP-1(7-37)OH的N末端高度特异。一种与碱性磷酸酶偶联的抗体能够与GLP-1的C末端特异结合,三者结合可形成一个完整的“三明治”式的结合。可以用一种叫做pNPP的碱性磷酸酶显色底物完成检测。所产生的颜色的深浅直接与存在于样本中免疫反应性的Val8-GLP-1(7-37)OH的浓度成正比。人血浆中Val8-GLP-1(7-37)OH量的数值可以从以Val8-GLP-1(7-37)OH作参考标准的标准曲线中读取。通过计算机程序,用加权的4参数逻辑运算对数据进行分析。检测样本中免疫反应性的Val8-GLP-1(7-37)OH的浓度使用标准曲线确定。
实例3-体外药效测定:
将能表达人的GLP-1受体的HEK-293 Aurora CRE-BLAM细胞接种于黑色亮底96孔平板中,密度为20,000至40,000个细胞/孔/100微升。接种之后,将培养基换为无血清的培养基。在接种后的第三天,将20ul含有不同浓度GLP-1激动剂的无血清培养基加入不同的孔中,从而绘制一条剂量反应曲线。通常,含有3纳摩尔至30纳摩尔GLP-1化合物的14倍稀释用于绘制剂量反应曲线,由此来确定EC50。在与GLP-1化合物共同孵育5小时之后,向孵育体系中加入20ul β-内酰胺酶底物(CCF2-AM-Aurora生物科技公司-产品编号100012),并继续孵育1小时,然后用细胞荧光检测仪测定荧光强度。
表1
化合物 | 与Val8-GLP-1(7-37)OH相比较得出的EC50值 |
Val8-GLP-1(7-37)OH | 1.0 |
Gly8-GLP-1(7-37)OH | 1.7 |
Val8-Tyr12-GLP-1(7-37)OH | 1.7 |
Val8-Tyr12-GLP-1(7-36)NH2 | 1.1 |
Val8Trp12-GLP-1(7-37)OH | 1.1 |
Val8-Leu16-GLP-1(7-37)OH | 1.1 |
Val8-Tyr16-GLP-1(7-37)OH | 2.5 |
Gly8-Glu22-GLP-1(7-37)OH | 2.2 |
Val8-Leu25-GLP-1(7-37)OH | 0.5 |
Val8-Glu30-GLP-1(7-37)OH | 0.7 |
Val8-His37-GLP-1(7-37)OH | 1.2 |
Val8-Tyr12-Tyr16-GLP-1(7-37)OH | 1.5 |
Val8-Trp12-Glu22-GLP-1(7-37)OH | 1.7 |
Val8-Tyr12-Glu22-GLP-1(7-37)OH | 2.7 |
Val8-Tyr16-Phe19-GLP-1(7-37)OH | 2.8 |
Val8-Tyr16-Glu22-GLP-1(7-37)OH | 3.6,3.8 |
Val8-Trp16-Glu22-GLP-1(7-37)OH | 4.9,4.6 |
Val8-Leu16-Glu22-GLP-1(7-37)OH | 4.3 |
Val8-Ile16-Glu22-GLP-1(7-37)OH | 3.3 |
Val8-Phe16-Glu22-GLP-1(7-37)OH | 2.3 |
Val8-Trp18-Glu22-GLP-1(7-37)OH | 3.2,6.6 |
Val8-Tyr18-Glu22-GLP-1(7-37)OH | 5.1,5.9 |
Val8-Phe18-Glu22-GLP-1(7-37)OH | 2.0 |
Val8-Ile18-Glu22-GLP-1(7-37)OH | 4.0 |
Val8-Lys18-Glu22-GLP-1(7-37)OH | 2.5 |
Val8-Trp19-Glu22-GLP-1(7-37)OH | 3.2 |
Val8-Phe19-Glu22-GLP-1(7-37)OH | 1.5 |
Val8-Phe20-Glu22-GLP-1(7-37)OH | 2.7 |
Val8-Glu22-Leu25-GLP-1(7-37)OH | 2.8 |
Val8-Glu22-Ile25-GLP-1(7-37)OH | 3.1 |
Val8-Glu22-Val25-GLP-1(7-37)OH | 4.7,2.9 |
Val8-Glu22-Ile27-GLP-1(7-37)OH | 2.0 |
Val8-Glu22-Ala27-GLP-1(7-37)OH | 2.2 |
Val8-Glu22-Ile33-GLP-1(7-37)OH | 4.7,3.8,3.4 |
Val8-Glu22-His37-GLP-1(7-37)OH | 4.7 |
Val8-Asp9-Ile11-Tyr16-Glu22-GLP-1(7-37)OH | 4.3 |
Val8-Tyr16-Trp19-Glu22-GLP-1(7-37)OH | 3.5 |
Val8-Trp16-Glu22-Val25-Ile33-GLP-1(7-37)OH | 5.O |
Val8-Trp16-Glu22-Ile33-GLP-1(7-37)OH | 4.1 |
Val8-Glu22-Val25-Ile33-GLP-1(7-37)OH | 4.9,5.8,6.7 |
Val8-Trp16-Glu22-Val25-GLP-1(7-37)OH | 4.4 |
序列表
<110>礼来公司
<120>胃轻瘫的治疗
<130>X-15632
<150>P15632
<151>2002-04-10
<160>2
<170>专利版本3.1
<210>1
<211>31
<212>PRT
<213>人类
<220>
<221>多种多样的特征
<222>(30)..(30)
<223>当在31位的Xaa不存在或是为Arg时,在30位的Xaa是Arg-NH2
<220>
<221>多种多样的特征
<222>(31)..(31)
<223>当在30位的Xaa是Arg时,在31位的Xaa不存在或是为Gly
<400>1
His Ala Glu Gly Thr Phe Thr Ser Asp Va1 Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Xaa Xaa
20 25 30
<210>2
<211>39
<212>PRT
<213>毒蜥sp.
<220>
<221>多种多样的特征
<222>(2)..(2)
<223>第2位的Xaa是Ser或Gly
<220>
<221>多种多样的特征
<222>(39)..(39)
<223>第39位的Xaa是Ser或Ser NH2
<220>
<221>多种多样的特征
<222>(3)..(3)
<223>第3位的Xaa是Asp或Glu
<400>2
His Xaa Xaa Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Xaa
35
Claims (17)
1.一种治疗胃轻瘫患者的方法,包括对所述患者施用有效量的GLP-1化合物。
2.权利要求1的方法,其中所述患者还患有糖尿病。
3.权利要求2的方法,其中所述患者患有2型糖尿病。
4.权利要求1至3中任何一项的方法,其中所述GLP-1化合物选自GLP-1(7-36)酰胺,GLP-1(7-37),GLP-1类似物和GLP-1衍生物。
5.权利要求1至3中任何一项的方法,其中所述GLP-1化合物选自Exendin-4,Exendin-4类似物和Exendin-4衍生物。
6.权利要求1至3中任何一项的方法,其中所述GLP-1化合物是GLP-1受体的激动剂。
7.权利要求1至3中任何一项的方法,其中所述GLP-1化合物是抗DPP-IV的类似物。
8.权利要求7的方法,其中所述GLP-1化合物是GLP-1类似物或在22位为谷氨酸的GLP-1衍生物。
9.权利要求7的方法,其中所述GLP-1化合物是在8位为缬氨酸或甘氨酸的GLP-1类似物。
10.权利要求1至3中任何一项的方法,其中所述GLP-1化合物是GLP-1衍生物。
11.权利要求10的方法,其中所述GLP-1衍生物是酰化的GLP-1类似物。
12.权利要求11的方法,其中所述GLP-1衍生物是Arg34Lys26-(N-ε-(γ-Glu(N-α-十六烷酰基)))-GLP-1(7-37)。
13.权利要求1至12中任意一项的方法,其中所述GLP-1化合物通过皮下注射给药。
14.权利要求1至12中任意一项的方法,其中所述GLP-1化合物通过口服给药。
15.权利要求1至12中任意一项的方法,其中所述GLP-1化合物通过颊部给药。
16.GLP-1化合物在制备用于治疗胃轻瘫的药物中的用途。
17.GLP-1化合物在制备用于权利要求1至15中任意一项的方法的药物中的用途。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US37165002P | 2002-04-10 | 2002-04-10 | |
US60/371,650 | 2002-04-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1735423A true CN1735423A (zh) | 2006-02-15 |
Family
ID=29250714
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA038080079A Pending CN1735423A (zh) | 2002-04-10 | 2003-03-27 | 胃轻瘫的治疗 |
Country Status (18)
Country | Link |
---|---|
US (1) | US20050164925A1 (zh) |
EP (1) | EP1496924A4 (zh) |
JP (1) | JP2005530732A (zh) |
KR (1) | KR20040098063A (zh) |
CN (1) | CN1735423A (zh) |
AU (1) | AU2003220403A1 (zh) |
BR (1) | BR0308904A (zh) |
CA (1) | CA2480858A1 (zh) |
EA (1) | EA200401345A1 (zh) |
EC (1) | ECSP045345A (zh) |
HR (1) | HRP20040939A2 (zh) |
IL (1) | IL164266A0 (zh) |
MX (1) | MXPA04009929A (zh) |
NO (1) | NO20044815L (zh) |
NZ (1) | NZ535684A (zh) |
PL (1) | PL373658A1 (zh) |
WO (1) | WO2003087139A2 (zh) |
ZA (1) | ZA200408111B (zh) |
Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8666495B2 (en) | 1999-03-05 | 2014-03-04 | Metacure Limited | Gastrointestinal methods and apparatus for use in treating disorders and controlling blood sugar |
US9101765B2 (en) | 1999-03-05 | 2015-08-11 | Metacure Limited | Non-immediate effects of therapy |
US8792985B2 (en) | 2003-07-21 | 2014-07-29 | Metacure Limited | Gastrointestinal methods and apparatus for use in treating disorders and controlling blood sugar |
US20070203058A1 (en) * | 2003-09-19 | 2007-08-30 | Novo Nordisk A/S | Novel Glp-1 Derivatives |
WO2005028516A2 (en) * | 2003-09-19 | 2005-03-31 | Novo Nordisk A/S | Albumin-binding derivatives of therapeutic peptides |
WO2006018851A2 (en) | 2004-08-18 | 2006-02-23 | Metacure Ltd. | Monitoring, analysis, and regulation of eating habits |
US9821158B2 (en) | 2005-02-17 | 2017-11-21 | Metacure Limited | Non-immediate effects of therapy |
WO2006087712A2 (en) | 2005-02-17 | 2006-08-24 | Metacure N.V. | Charger with data transfer capabilities |
EP1863521B1 (en) | 2005-03-18 | 2014-05-07 | Novo Nordisk A/S | Extended glp-1 compounds |
TWI362392B (en) | 2005-03-18 | 2012-04-21 | Novo Nordisk As | Acylated glp-1 compounds |
US8265758B2 (en) * | 2005-03-24 | 2012-09-11 | Metacure Limited | Wireless leads for gastrointestinal tract applications |
US8463404B2 (en) | 2005-03-24 | 2013-06-11 | Metacure Limited | Electrode assemblies, tools, and methods for gastric wall implantation |
EP1890763A4 (en) | 2005-06-02 | 2017-05-03 | Metacure Limited | Gi lead implantation |
US8442841B2 (en) * | 2005-10-20 | 2013-05-14 | Matacure N.V. | Patient selection method for assisting weight loss |
US8295932B2 (en) | 2005-12-05 | 2012-10-23 | Metacure Limited | Ingestible capsule for appetite regulation |
AU2012203915B9 (en) * | 2006-04-20 | 2014-10-09 | Amgen Inc. | GLP-1 compounds |
JP2009534423A (ja) * | 2006-04-20 | 2009-09-24 | アムジェン インコーポレイテッド | Glp−1化合物 |
WO2008139463A2 (en) * | 2007-05-09 | 2008-11-20 | Metacure Ltd. | Analysis and regulation of food intake |
US8423130B2 (en) * | 2008-05-09 | 2013-04-16 | Metacure Limited | Optimization of thresholds for eating detection |
JP5977945B2 (ja) | 2008-08-06 | 2016-08-24 | ノヴォ・ノルディスク・ヘルス・ケア・アーゲー | 長期のインビボ有効性を有するコンジュゲートタンパク質 |
ES2542202T3 (es) | 2009-01-22 | 2015-08-03 | Novo Nordisk Health Care Ag | Compuestos de hormonas de crecimiento estables |
JP6086528B2 (ja) | 2009-08-06 | 2017-03-01 | ノヴォ・ノルディスク・ヘルス・ケア・アーゲー | 長期のインビボ有効性を有する成長ホルモン |
US8642548B2 (en) * | 2009-08-07 | 2014-02-04 | Mannkind Corporation | Val (8) GLP-1 composition and method for treating functional dyspepsia and/or irritable bowel syndrome |
JP5875527B2 (ja) | 2010-01-22 | 2016-03-02 | ノヴォ・ノルディスク・ヘルス・ケア・アーゲー | in−vivoにおける効力が延長された成長ホルモン |
AU2011208620B2 (en) | 2010-01-22 | 2015-04-16 | Novo Nordisk Health Care Ag | Stable growth hormone compounds |
WO2011092710A2 (en) * | 2010-02-01 | 2011-08-04 | Metacure Limited | Gastrointestinal electrical therapy |
CA2793715A1 (en) | 2010-04-30 | 2011-11-03 | Sanwa Kagaku Kenkyusho Co., Ltd. | Peptide for improving in vivo stability of physiologically active substance or the like and physiologically active substance with improved in vivo stability |
UA116217C2 (uk) | 2012-10-09 | 2018-02-26 | Санофі | Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону |
RU2652783C2 (ru) | 2012-12-21 | 2018-05-03 | Санофи | Двойные агонисты glp1/gip или тройные агонисты glp1/gip/глюкагона |
JP6464145B2 (ja) | 2013-04-05 | 2019-02-06 | ノヴォ・ノルディスク・ヘルス・ケア・アーゲー | 成長ホルモン化合物製剤 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6268343B1 (en) * | 1996-08-30 | 2001-07-31 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
JP2002510193A (ja) * | 1997-03-31 | 2002-04-02 | イーライ・リリー・アンド・カンパニー | グルカゴン様ペプチド−1類似体 |
IL142707A0 (en) * | 2000-04-27 | 2002-03-10 | Pfizer Prod Inc | Methods of treating obesity using a neurotensin receptor ligand |
-
2003
- 2003-03-27 EA EA200401345A patent/EA200401345A1/ru unknown
- 2003-03-27 BR BR0308904-5A patent/BR0308904A/pt not_active IP Right Cessation
- 2003-03-27 KR KR10-2004-7016025A patent/KR20040098063A/ko not_active Application Discontinuation
- 2003-03-27 EP EP03716707A patent/EP1496924A4/en not_active Withdrawn
- 2003-03-27 CN CNA038080079A patent/CN1735423A/zh active Pending
- 2003-03-27 NZ NZ535684A patent/NZ535684A/xx unknown
- 2003-03-27 JP JP2003584094A patent/JP2005530732A/ja active Pending
- 2003-03-27 WO PCT/US2003/008457 patent/WO2003087139A2/en not_active Application Discontinuation
- 2003-03-27 US US10/508,762 patent/US20050164925A1/en not_active Abandoned
- 2003-03-27 AU AU2003220403A patent/AU2003220403A1/en not_active Abandoned
- 2003-03-27 MX MXPA04009929A patent/MXPA04009929A/es not_active Application Discontinuation
- 2003-03-27 CA CA002480858A patent/CA2480858A1/en not_active Abandoned
- 2003-03-27 PL PL03373658A patent/PL373658A1/xx unknown
- 2003-03-27 IL IL16426603A patent/IL164266A0/xx unknown
-
2004
- 2004-10-07 HR HRP20040939 patent/HRP20040939A2/hr not_active Application Discontinuation
- 2004-10-07 ZA ZA200408111A patent/ZA200408111B/xx unknown
- 2004-10-08 EC EC2004005345A patent/ECSP045345A/es unknown
- 2004-11-05 NO NO20044815A patent/NO20044815L/no unknown
Also Published As
Publication number | Publication date |
---|---|
EP1496924A2 (en) | 2005-01-19 |
WO2003087139A2 (en) | 2003-10-23 |
KR20040098063A (ko) | 2004-11-18 |
JP2005530732A (ja) | 2005-10-13 |
BR0308904A (pt) | 2005-05-03 |
PL373658A1 (en) | 2005-09-05 |
ECSP045345A (es) | 2006-04-19 |
IL164266A0 (en) | 2005-12-18 |
AU2003220403A1 (en) | 2003-10-27 |
HRP20040939A2 (en) | 2004-12-31 |
US20050164925A1 (en) | 2005-07-28 |
MXPA04009929A (es) | 2006-03-10 |
ZA200408111B (en) | 2005-10-07 |
WO2003087139A3 (en) | 2004-01-08 |
EP1496924A4 (en) | 2007-05-30 |
NZ535684A (en) | 2006-03-31 |
EA200401345A1 (ru) | 2005-08-25 |
CA2480858A1 (en) | 2003-10-23 |
NO20044815L (no) | 2005-01-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1735423A (zh) | 胃轻瘫的治疗 | |
KR101383493B1 (ko) | 정신의학적 질환 및 장애를 치료하기 위한 아밀린 및아밀린 효능제 | |
CN1268640C (zh) | 胰高血糖素样肽-2的类似物 | |
RU2533217C2 (ru) | Препарат, содержащий инсулин, никотинамид и аминокислоту | |
US7238663B2 (en) | Pre-mixes of GLP-1 and basal insulin | |
AU2007267833B2 (en) | Composition and methods for treatment of congestive heart failure | |
ES2293688T3 (es) | Nuevos compuestos analogos de la exendina. | |
EP1888103B1 (en) | Use of glp-1, exendin and agonists thereof to delay or prevent cardiac remodeling | |
US6136784A (en) | Amylin agonist pharmaceutical compositions containing insulin | |
US20030087820A1 (en) | Novel exendin agonist formulations and methods of administration thereof | |
CN105722854B (zh) | 用于治疗疾病和病症的降钙素模拟物 | |
EP0717635A1 (en) | Methods for regulating gastrointestinal motility | |
CN106715466A (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 | |
KR20080106950A (ko) | 정신의학적 질환 및 장애를 치료하기 위한 아밀린 및 아밀린 효능제 | |
Garber | Incretin therapy–present and future | |
JP2014501239A (ja) | インスリン、ニコチンアミドおよびアミノ酸を含む製剤 | |
CN1835760A (zh) | 用于治疗和/或预防与2型糖尿病有关的功能障碍的组合物 | |
WO1999034764A2 (en) | Amylin agonist pharmaceutical compositions containing insulin | |
EP1051141A1 (en) | Amylin agonist pharmaceutical compositions containing insulin | |
CN103566354B (zh) | 含有glp‑1类似物的衍生物或其可药用盐的药物组合物 | |
Kaur et al. | Hormones and Hormones Antagonists | |
Liu et al. | Oral Delivery of Protein and Peptide Therapeutics: PK/PD and Metabolism Considerations | |
Fineman et al. | AC2993 (Synthetic Exendin-4) Improved Glycemic Control in Patients With Type 2 Diabetes During 28 Days of Treatment in a Multicenter, Randomized, Triple-Blind, Placebo-Controlled Study | |
Liu et al. | Oral Delivery of Protein and Peptide Therapeutics: PK/PD and Metabolism | |
AU2002313662A1 (en) | Pre-mixes of GLP-1 and basal insulin |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |