TW201326194A - Glp-1胃泌素受體促效劑肽結合物 - Google Patents
Glp-1胃泌素受體促效劑肽結合物 Download PDFInfo
- Publication number
- TW201326194A TW201326194A TW101140873A TW101140873A TW201326194A TW 201326194 A TW201326194 A TW 201326194A TW 101140873 A TW101140873 A TW 101140873A TW 101140873 A TW101140873 A TW 101140873A TW 201326194 A TW201326194 A TW 201326194A
- Authority
- TW
- Taiwan
- Prior art keywords
- 8ado
- pharmaceutically acceptable
- glu
- solvate
- disease
- Prior art date
Links
- 239000000863 peptide conjugate Substances 0.000 title claims abstract description 143
- 108010089448 Cholecystokinin B Receptor Proteins 0.000 title description 9
- 102000052874 Gastrin receptors Human genes 0.000 title description 4
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 title 1
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 title 1
- 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 1
- 239000000018 receptor agonist Substances 0.000 title 1
- 229940044601 receptor agonist Drugs 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 71
- 201000010099 disease Diseases 0.000 claims abstract description 63
- 238000011282 treatment Methods 0.000 claims abstract description 62
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 35
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 84
- 150000003839 salts Chemical class 0.000 claims description 83
- 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 claims description 79
- 239000008103 glucose Substances 0.000 claims description 79
- 238000000034 method Methods 0.000 claims description 73
- 239000012453 solvate Substances 0.000 claims description 70
- 210000004369 blood Anatomy 0.000 claims description 55
- 239000008280 blood Substances 0.000 claims description 55
- 150000001875 compounds Chemical class 0.000 claims description 40
- -1 ethyl hydrazino, decyl Chemical group 0.000 claims description 40
- 239000003981 vehicle Substances 0.000 claims description 40
- 239000003814 drug Substances 0.000 claims description 36
- 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 claims description 36
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 claims description 33
- 102400000921 Gastrin Human genes 0.000 claims description 31
- 208000008589 Obesity Diseases 0.000 claims description 31
- 239000003795 chemical substances by application Substances 0.000 claims description 31
- 229940079593 drug Drugs 0.000 claims description 26
- 235000020824 obesity Nutrition 0.000 claims description 26
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 26
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 25
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 21
- 230000037396 body weight Effects 0.000 claims description 19
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 17
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 16
- 102000004877 Insulin Human genes 0.000 claims description 16
- 108090001061 Insulin Proteins 0.000 claims description 16
- 229940125396 insulin Drugs 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 15
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 15
- 208000001280 Prediabetic State Diseases 0.000 claims description 15
- 239000000556 agonist Substances 0.000 claims description 15
- 230000001939 inductive effect Effects 0.000 claims description 15
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 14
- 201000001320 Atherosclerosis Diseases 0.000 claims description 12
- 206010020772 Hypertension Diseases 0.000 claims description 12
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 12
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 12
- 201000011510 cancer Diseases 0.000 claims description 12
- 201000001421 hyperglycemia Diseases 0.000 claims description 12
- 230000004083 survival effect Effects 0.000 claims description 12
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 11
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 11
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 11
- 102400000922 Gastrin-6 Human genes 0.000 claims description 11
- 101800002467 Gastrin-6 Proteins 0.000 claims description 11
- 208000006011 Stroke Diseases 0.000 claims description 11
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 11
- 230000001965 increasing effect Effects 0.000 claims description 11
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 10
- 208000005764 Peripheral Arterial Disease Diseases 0.000 claims description 10
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 10
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 10
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 10
- 230000027455 binding Effects 0.000 claims description 10
- 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 claims description 10
- 208000029078 coronary artery disease Diseases 0.000 claims description 10
- 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 claims description 10
- 201000006370 kidney failure Diseases 0.000 claims description 10
- 235000019786 weight gain Nutrition 0.000 claims description 10
- 238000009739 binding Methods 0.000 claims description 9
- 230000035755 proliferation Effects 0.000 claims description 9
- 206010009944 Colon cancer Diseases 0.000 claims description 8
- 206010054805 Macroangiopathy Diseases 0.000 claims description 8
- 230000006907 apoptotic process Effects 0.000 claims description 8
- 230000000923 atherogenic effect Effects 0.000 claims description 8
- 208000029742 colonic neoplasm Diseases 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 8
- 230000009467 reduction Effects 0.000 claims description 8
- 229940124530 sulfonamide Drugs 0.000 claims description 8
- 150000003456 sulfonamides Chemical class 0.000 claims description 8
- 230000004584 weight gain Effects 0.000 claims description 8
- 230000001737 promoting effect Effects 0.000 claims description 7
- 208000018556 stomach disease Diseases 0.000 claims description 7
- 230000004580 weight loss Effects 0.000 claims description 7
- 108010011459 Exenatide Proteins 0.000 claims description 6
- 206010022489 Insulin Resistance Diseases 0.000 claims description 6
- 208000031773 Insulin resistance syndrome Diseases 0.000 claims description 6
- 244000137850 Marrubium vulgare Species 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 230000000112 colonic effect Effects 0.000 claims description 6
- 208000020694 gallbladder disease Diseases 0.000 claims description 6
- 230000017074 necrotic cell death Effects 0.000 claims description 6
- 230000009707 neogenesis Effects 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 claims description 5
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide 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](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 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 claims description 5
- 101001002317 Homo sapiens Gastrin Proteins 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 239000005557 antagonist Substances 0.000 claims description 5
- 208000012696 congenital leptin deficiency Diseases 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 5
- 229960003105 metformin Drugs 0.000 claims description 5
- 208000001022 morbid obesity Diseases 0.000 claims description 5
- 201000002859 sleep apnea Diseases 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- 241000024188 Andala Species 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 229960001519 exenatide Drugs 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 230000008929 regeneration Effects 0.000 claims description 4
- 238000011069 regeneration method Methods 0.000 claims description 4
- NKOHRVBBQISBSB-UHFFFAOYSA-N 5-[(4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione Chemical compound C1=CC(O)=CC=C1CC1C(=O)NC(=O)S1 NKOHRVBBQISBSB-UHFFFAOYSA-N 0.000 claims description 3
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 claims description 3
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims description 3
- 241000270431 Heloderma suspectum Species 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 238000002648 combination therapy Methods 0.000 claims description 3
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 3
- 229940126409 proton pump inhibitor Drugs 0.000 claims description 3
- 239000000612 proton pump inhibitor Substances 0.000 claims description 3
- DFZVZEMNPGABKO-ZETCQYMHSA-N (2s)-2-amino-3-pyridin-3-ylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CN=C1 DFZVZEMNPGABKO-ZETCQYMHSA-N 0.000 claims description 2
- 239000005541 ACE inhibitor Substances 0.000 claims description 2
- 102000008873 Angiotensin II receptor Human genes 0.000 claims description 2
- 108050000824 Angiotensin II receptor Proteins 0.000 claims description 2
- YNXLOPYTAAFMTN-SBUIBGKBSA-N C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 Chemical compound C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 YNXLOPYTAAFMTN-SBUIBGKBSA-N 0.000 claims description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 2
- 101000581402 Homo sapiens Melanin-concentrating hormone receptor 1 Proteins 0.000 claims description 2
- 229940086609 Lipase inhibitor Drugs 0.000 claims description 2
- 102100027375 Melanin-concentrating hormone receptor 1 Human genes 0.000 claims description 2
- 102100023724 Melanocortin receptor 4 Human genes 0.000 claims description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 2
- 108010088847 Peptide YY Proteins 0.000 claims description 2
- 102100029909 Peptide YY Human genes 0.000 claims description 2
- 108010021436 Type 4 Melanocortin Receptor Proteins 0.000 claims description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 2
- 239000002876 beta blocker Substances 0.000 claims description 2
- 229940097320 beta blocking agent Drugs 0.000 claims description 2
- 210000004204 blood vessel Anatomy 0.000 claims description 2
- 239000000480 calcium channel blocker Substances 0.000 claims description 2
- 230000004663 cell proliferation Effects 0.000 claims description 2
- 235000012000 cholesterol Nutrition 0.000 claims description 2
- 230000001906 cholesterol absorption Effects 0.000 claims description 2
- 239000002934 diuretic Substances 0.000 claims description 2
- 229940030606 diuretics Drugs 0.000 claims description 2
- 229940125753 fibrate Drugs 0.000 claims description 2
- 239000004026 insulin derivative Substances 0.000 claims description 2
- 229960003512 nicotinic acid Drugs 0.000 claims description 2
- 235000001968 nicotinic acid Nutrition 0.000 claims description 2
- 239000011664 nicotinic acid Substances 0.000 claims description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims 7
- 208000030090 Acute Disease Diseases 0.000 claims 5
- 210000004153 islets of langerhan Anatomy 0.000 claims 2
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 claims 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 claims 1
- 102100033868 Cannabinoid receptor 1 Human genes 0.000 claims 1
- 101710187010 Cannabinoid receptor 1 Proteins 0.000 claims 1
- 102000004190 Enzymes Human genes 0.000 claims 1
- 108090000790 Enzymes Proteins 0.000 claims 1
- 102000006419 Glucagon-Like Peptide Receptors Human genes 0.000 claims 1
- 108010083749 Glucagon-Like Peptide Receptors Proteins 0.000 claims 1
- 239000004471 Glycine Substances 0.000 claims 1
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 claims 1
- 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 1
- 229960002449 glycine Drugs 0.000 claims 1
- 208000019622 heart disease Diseases 0.000 claims 1
- 125000004857 imidazopyridinyl group Chemical class N1C(=NC2=C1C=CC=N2)* 0.000 claims 1
- 208000035475 disorder Diseases 0.000 abstract description 8
- 239000000562 conjugate Substances 0.000 abstract description 7
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 35
- 230000000694 effects Effects 0.000 description 35
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 34
- 125000006850 spacer group Chemical group 0.000 description 33
- 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 31
- 108010019598 Liraglutide Proteins 0.000 description 31
- 229960002701 liraglutide Drugs 0.000 description 30
- 125000003275 alpha amino acid group Chemical group 0.000 description 29
- 239000000872 buffer Substances 0.000 description 29
- 239000000859 incretin Substances 0.000 description 29
- 125000001424 substituent group Chemical group 0.000 description 28
- 239000000203 mixture Substances 0.000 description 24
- 108010052343 Gastrins Proteins 0.000 description 23
- 235000001014 amino acid Nutrition 0.000 description 23
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 22
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 21
- 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 21
- 150000001413 amino acids Chemical class 0.000 description 20
- 102000004196 processed proteins & peptides Human genes 0.000 description 20
- 230000002829 reductive effect Effects 0.000 description 20
- 241000699670 Mus sp. Species 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 18
- 238000007920 subcutaneous administration Methods 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 16
- 229920005989 resin Polymers 0.000 description 16
- 239000011347 resin Substances 0.000 description 16
- 102000005962 receptors Human genes 0.000 description 14
- 108020003175 receptors Proteins 0.000 description 14
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 13
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 13
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 13
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 13
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 13
- 229960003104 ornithine Drugs 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 11
- 229940125833 compound 23 Drugs 0.000 description 11
- 238000007410 oral glucose tolerance test Methods 0.000 description 11
- 230000001225 therapeutic effect Effects 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 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 10
- 238000006467 substitution reaction Methods 0.000 description 10
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 9
- 101800001982 Cholecystokinin Proteins 0.000 description 9
- 102100025841 Cholecystokinin Human genes 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 230000004071 biological effect Effects 0.000 description 9
- 229940107137 cholecystokinin Drugs 0.000 description 9
- 101001015516 Homo sapiens Glucagon-like peptide 1 receptor Proteins 0.000 description 8
- 230000009471 action Effects 0.000 description 8
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 8
- 239000012634 fragment Substances 0.000 description 8
- 125000001183 hydrocarbyl group Chemical group 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 229920001184 polypeptide Polymers 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 101800000285 Big gastrin Proteins 0.000 description 7
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 7
- 150000007970 thio esters Chemical class 0.000 description 7
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 6
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 6
- 229960002685 biotin Drugs 0.000 description 6
- 229940095074 cyclic amp Drugs 0.000 description 6
- 108010066264 gastrin 17 Proteins 0.000 description 6
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 125000005647 linker group Chemical group 0.000 description 6
- 125000004430 oxygen atom Chemical group O* 0.000 description 6
- 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 6
- 235000000346 sugar Nutrition 0.000 description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 6
- 125000004434 sulfur atom Chemical group 0.000 description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 description 6
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 102100036016 Gastrin/cholecystokinin type B receptor Human genes 0.000 description 5
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 5
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 5
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 5
- 102000015779 HDL Lipoproteins Human genes 0.000 description 5
- 108010010234 HDL Lipoproteins Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 235000020958 biotin Nutrition 0.000 description 5
- 239000011616 biotin Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 230000002503 metabolic effect Effects 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000007790 solid phase Substances 0.000 description 5
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 4
- 102400000948 Big gastrin Human genes 0.000 description 4
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 4
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 102000007330 LDL Lipoproteins Human genes 0.000 description 4
- 108010007622 LDL Lipoproteins Proteins 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 238000000540 analysis of variance Methods 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 230000037406 food intake Effects 0.000 description 4
- 235000012631 food intake Nutrition 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 238000001543 one-way ANOVA Methods 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 238000010647 peptide synthesis reaction Methods 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 238000013293 zucker diabetic fatty rat Methods 0.000 description 4
- 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 3
- FFOYZGOZWLCJDO-VHEIIQRDSA-N (4s,5r)-3-[(2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropanoyl]-2,2,5-trimethyl-1,3-oxazolidine-4-carboxylic acid Chemical compound OC(=O)[C@@H]1[C@@H](C)OC(C)(C)N1C(=O)[C@@H](NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)CC1=CC=CC=C1 FFOYZGOZWLCJDO-VHEIIQRDSA-N 0.000 description 3
- 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 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 3
- 101800004295 Glucagon-like peptide 1(7-36) Proteins 0.000 description 3
- 239000004366 Glucose oxidase Substances 0.000 description 3
- 108010015776 Glucose oxidase Proteins 0.000 description 3
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 3
- 108010014663 Glycated Hemoglobin A Proteins 0.000 description 3
- 101001021397 Homo sapiens Gastrin/cholecystokinin type B receptor Proteins 0.000 description 3
- XVVOERDUTLJJHN-UHFFFAOYSA-N Lixisenatide Chemical compound C=1NC2=CC=CC=C2C=1CC(C(=O)NC(CC(C)C)C(=O)NC(CCCCN)C(=O)NC(CC(N)=O)C(=O)NCC(=O)NCC(=O)N1C(CCC1)C(=O)NC(CO)C(=O)NC(CO)C(=O)NCC(=O)NC(C)C(=O)N1C(CCC1)C(=O)N1C(CCC1)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)CC)NC(=O)C(NC(=O)C(CC(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(CCC(O)=O)NC(=O)C(CCC(O)=O)NC(=O)C(CCSC)NC(=O)C(CCC(N)=O)NC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)C(CC(O)=O)NC(=O)C(CO)NC(=O)C(NC(=O)C(CC=1C=CC=CC=1)NC(=O)C(NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)CNC(=O)C(N)CC=1NC=NC=1)C(C)O)C(C)O)C(C)C)CC1=CC=CC=C1 XVVOERDUTLJJHN-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- VHWBWHBJEXGPNM-UHFFFAOYSA-N N(2)-(2,4-dichlorophenyl)-N-(7-{[(2,4-dichlorophenyl)amino]sulfonyl}-1-oxo-1,2-dihydronaphthalen-2-yl)glycinamide Chemical compound ClC1=CC(Cl)=CC=C1NCC(=O)NC1C(=O)C2=CC(S(=O)(=O)NC=3C(=CC(Cl)=CC=3)Cl)=CC=C2C=C1 VHWBWHBJEXGPNM-UHFFFAOYSA-N 0.000 description 3
- 206010033307 Overweight Diseases 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- 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 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- 229930003756 Vitamin B7 Natural products 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 235000019789 appetite Nutrition 0.000 description 3
- 230000036528 appetite Effects 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000000090 biomarker Substances 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 235000019577 caloric intake Nutrition 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229940125542 dual agonist Drugs 0.000 description 3
- 230000007937 eating Effects 0.000 description 3
- 235000005686 eating Nutrition 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 230000007515 enzymatic degradation Effects 0.000 description 3
- 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 3
- 235000019420 glucose oxidase Nutrition 0.000 description 3
- 229940116332 glucose oxidase Drugs 0.000 description 3
- 150000003278 haem Chemical class 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 230000003914 insulin secretion Effects 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 108010004367 lixisenatide Proteins 0.000 description 3
- 229960001093 lixisenatide Drugs 0.000 description 3
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 3
- 208000030159 metabolic disease Diseases 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 239000008177 pharmaceutical agent Substances 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- RZIMNEGTIDYAGZ-HNSJZBNRSA-N pro-gastrin Chemical compound N([C@@H](CC(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N1CCC[C@H]1C(=O)NCC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N1CCC[C@H]1C(=O)NCC(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=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)C(=O)[C@@H]1CCC(=O)N1 RZIMNEGTIDYAGZ-HNSJZBNRSA-N 0.000 description 3
- 210000003296 saliva Anatomy 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 235000011912 vitamin B7 Nutrition 0.000 description 3
- 239000011735 vitamin B7 Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- IOQORVDNYPOZPL-VQTJNVASSA-N (5S,6R)-5-(4-chlorophenyl)-6-cyclopropyl-3-[6-methoxy-5-(4-methylimidazol-1-yl)pyridin-2-yl]-5,6-dihydro-2H-1,2,4-oxadiazine Chemical compound ClC1=CC=C(C=C1)[C@@H]1NC(=NO[C@@H]1C1CC1)C1=NC(=C(C=C1)N1C=NC(=C1)C)OC IOQORVDNYPOZPL-VQTJNVASSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 101800004266 Glucagon-like peptide 1(7-37) Proteins 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 241000270453 Heloderma horridum Species 0.000 description 2
- 101000581815 Homo sapiens Regenerating islet-derived protein 3-alpha Proteins 0.000 description 2
- 102000003996 Interferon-beta Human genes 0.000 description 2
- 108090000467 Interferon-beta Proteins 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- 241000270322 Lepidosauria Species 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 description 2
- 108010076504 Protein Sorting Signals Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 108010086019 Secretin Proteins 0.000 description 2
- 102100037505 Secretin Human genes 0.000 description 2
- 229940100389 Sulfonylurea Drugs 0.000 description 2
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 238000003016 alphascreen Methods 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229940125708 antidiabetic agent Drugs 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229960002537 betamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 229940084891 byetta Drugs 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 150000001860 citric acid derivatives Chemical class 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940126540 compound 41 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 150000001924 cycloalkanes Chemical class 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000002716 delivery method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- MUCZHBLJLSDCSD-UHFFFAOYSA-N diisopropyl fluorophosphate Chemical compound CC(C)OP(F)(=O)OC(C)C MUCZHBLJLSDCSD-UHFFFAOYSA-N 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 230000030136 gastric emptying Effects 0.000 description 2
- 208000004104 gestational diabetes Diseases 0.000 description 2
- 230000002641 glycemic effect Effects 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 150000002338 glycosides Chemical class 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 102000004241 human proIslet peptide Human genes 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
- 230000002209 hydrophobic effect Effects 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 229960001388 interferon-beta Drugs 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 108010091718 peptide L Proteins 0.000 description 2
- 239000000813 peptide hormone Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 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 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000003259 recombinant expression Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 206010038464 renal hypertension Diseases 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229960002101 secretin Drugs 0.000 description 2
- OWMZNFCDEHGFEP-NFBCVYDUSA-N secretin human Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(N)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 OWMZNFCDEHGFEP-NFBCVYDUSA-N 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- 125000002653 sulfanylmethyl group Chemical group [H]SC([H])([H])[*] 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- RJMIEHBSYVWVIN-LLVKDONJSA-N (2r)-2-[4-(3-oxo-1h-isoindol-2-yl)phenyl]propanoic acid Chemical compound C1=CC([C@H](C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-LLVKDONJSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- 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 1
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 1
- GUHPRPJDBZHYCJ-SECBINFHSA-N (2s)-2-(5-benzoylthiophen-2-yl)propanoic acid Chemical compound S1C([C@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CC=C1 GUHPRPJDBZHYCJ-SECBINFHSA-N 0.000 description 1
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- GOPWHXPXSPIIQZ-FQEVSTJZSA-N (4s)-4-(9h-fluoren-9-ylmethoxycarbonylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCC(O)=O)C(=O)OC(C)(C)C)C3=CC=CC=C3C2=C1 GOPWHXPXSPIIQZ-FQEVSTJZSA-N 0.000 description 1
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- HBOMLICNUCNMMY-KJFJCRTCSA-N 1-[(4s,5s)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1C1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-KJFJCRTCSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 1
- KLIVRBFRQSOGQI-UHFFFAOYSA-N 2-(11-oxo-6h-benzo[c][1]benzothiepin-3-yl)acetic acid Chemical compound S1CC2=CC=CC=C2C(=O)C2=CC=C(CC(=O)O)C=C12 KLIVRBFRQSOGQI-UHFFFAOYSA-N 0.000 description 1
- MYQXHLQMZLTSDB-UHFFFAOYSA-N 2-(2-ethyl-2,3-dihydro-1-benzofuran-5-yl)acetic acid Chemical compound OC(=O)CC1=CC=C2OC(CC)CC2=C1 MYQXHLQMZLTSDB-UHFFFAOYSA-N 0.000 description 1
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 1
- DCXHLPGLBYHNMU-UHFFFAOYSA-N 2-[1-(4-azidobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(N=[N+]=[N-])C=C1 DCXHLPGLBYHNMU-UHFFFAOYSA-N 0.000 description 1
- RUVRGYVESPRHSZ-UHFFFAOYSA-N 2-[2-(2-azaniumylethoxy)ethoxy]acetate Chemical compound NCCOCCOCC(O)=O RUVRGYVESPRHSZ-UHFFFAOYSA-N 0.000 description 1
- APBSKHYXXKHJFK-UHFFFAOYSA-N 2-[2-(4-chlorophenyl)-1,3-thiazol-4-yl]acetic acid Chemical compound OC(=O)CC1=CSC(C=2C=CC(Cl)=CC=2)=N1 APBSKHYXXKHJFK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- TYCOFFBAZNSQOJ-UHFFFAOYSA-N 2-[4-(3-fluorophenyl)phenyl]propanoic acid Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC(F)=C1 TYCOFFBAZNSQOJ-UHFFFAOYSA-N 0.000 description 1
- JIEKMACRVQTPRC-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)-2-phenyl-5-thiazolyl]acetic acid Chemical compound OC(=O)CC=1SC(C=2C=CC=CC=2)=NC=1C1=CC=C(Cl)C=C1 JIEKMACRVQTPRC-UHFFFAOYSA-N 0.000 description 1
- WGDADRBTCPGSDG-UHFFFAOYSA-N 2-[[4,5-bis(4-chlorophenyl)-1,3-oxazol-2-yl]sulfanyl]propanoic acid Chemical compound O1C(SC(C)C(O)=O)=NC(C=2C=CC(Cl)=CC=2)=C1C1=CC=C(Cl)C=C1 WGDADRBTCPGSDG-UHFFFAOYSA-N 0.000 description 1
- XKSAJZSJKURQRX-UHFFFAOYSA-N 2-acetyloxy-5-(4-fluorophenyl)benzoic acid Chemical compound C1=C(C(O)=O)C(OC(=O)C)=CC=C1C1=CC=C(F)C=C1 XKSAJZSJKURQRX-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- ILYSAKHOYBPSPC-UHFFFAOYSA-N 2-phenylbenzoic acid Chemical class OC(=O)C1=CC=CC=C1C1=CC=CC=C1 ILYSAKHOYBPSPC-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- SYCHUQUJURZQMO-UHFFFAOYSA-N 4-hydroxy-2-methyl-1,1-dioxo-n-(1,3-thiazol-2-yl)-1$l^{6},2-benzothiazine-3-carboxamide Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=CS1 SYCHUQUJURZQMO-UHFFFAOYSA-N 0.000 description 1
- PJJGZPJJTHBVMX-UHFFFAOYSA-N 5,7-Dihydroxyisoflavone Chemical compound C=1C(O)=CC(O)=C(C2=O)C=1OC=C2C1=CC=CC=C1 PJJGZPJJTHBVMX-UHFFFAOYSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- UQXNEWQGGVUVQA-UHFFFAOYSA-N 8-aminooctanoic acid Chemical compound NCCCCCCCC(O)=O UQXNEWQGGVUVQA-UHFFFAOYSA-N 0.000 description 1
- 208000004611 Abdominal Obesity Diseases 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical compound CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- XVPZRKIQCKKYNE-UHFFFAOYSA-N Arborine Chemical compound N=1C(=O)C2=CC=CC=C2N(C)C=1CC1=CC=CC=C1 XVPZRKIQCKKYNE-UHFFFAOYSA-N 0.000 description 1
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 108010074051 C-Reactive Protein Proteins 0.000 description 1
- 102100032752 C-reactive protein Human genes 0.000 description 1
- 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 1
- BXHINFVOFJNCFP-UFLZEWODSA-N C=N.OC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@H]12 Chemical compound C=N.OC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@H]12 BXHINFVOFJNCFP-UFLZEWODSA-N 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000018208 Cannabinoid Receptor Human genes 0.000 description 1
- 108050007331 Cannabinoid receptor Proteins 0.000 description 1
- 102000011632 Caseins Human genes 0.000 description 1
- 108010076119 Caseins Proteins 0.000 description 1
- 206010065941 Central obesity Diseases 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- OIRAEJWYWSAQNG-UHFFFAOYSA-N Clidanac Chemical compound ClC=1C=C2C(C(=O)O)CCC2=CC=1C1CCCCC1 OIRAEJWYWSAQNG-UHFFFAOYSA-N 0.000 description 1
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- RBBWCVQDXDFISW-UHFFFAOYSA-N Feprazone Chemical compound O=C1C(CC=C(C)C)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 RBBWCVQDXDFISW-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 210000000712 G cell Anatomy 0.000 description 1
- 102400000920 Gastrin-14 Human genes 0.000 description 1
- 241000237858 Gastropoda Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102400000326 Glucagon-like peptide 2 Human genes 0.000 description 1
- 101800000221 Glucagon-like peptide 2 Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010089308 Insulin Detemir Proteins 0.000 description 1
- 108010057186 Insulin Glargine Proteins 0.000 description 1
- 108010065920 Insulin Lispro Proteins 0.000 description 1
- FYZPCMFQCNBYCY-WIWKJPBBSA-N Insulin degludec Chemical compound CC[C@H](C)[C@H](NC(=O)CN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc3ccccc3)C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](Cc3c[nH]cn3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC2=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC(O)=O)C(O)=O)C(O)=O)NC1=O)[C@@H](C)O)[C@@H](C)CC FYZPCMFQCNBYCY-WIWKJPBBSA-N 0.000 description 1
- COCFEDIXXNGUNL-RFKWWTKHSA-N Insulin glargine Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)NCC(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 COCFEDIXXNGUNL-RFKWWTKHSA-N 0.000 description 1
- 108010005716 Interferon beta-1a Proteins 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- GHSJKUNUIHUPDF-BYPYZUCNSA-N L-thialysine Chemical compound NCCSC[C@H](N)C(O)=O GHSJKUNUIHUPDF-BYPYZUCNSA-N 0.000 description 1
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102000016267 Leptin Human genes 0.000 description 1
- 108010092277 Leptin Proteins 0.000 description 1
- 206010024264 Lethargy Diseases 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 125000000729 N-terminal amino-acid group Chemical group 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- JZFPYUNJRRFVQU-UHFFFAOYSA-N Niflumic acid Chemical compound OC(=O)C1=CC=CN=C1NC1=CC=CC(C(F)(F)F)=C1 JZFPYUNJRRFVQU-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 101710126321 Pancreatic trypsin inhibitor Proteins 0.000 description 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 1
- 101710176384 Peptide 1 Proteins 0.000 description 1
- 101710117971 Peptide Y Proteins 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 description 1
- 102100039418 Plasminogen activator inhibitor 1 Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920000805 Polyaspartic acid Polymers 0.000 description 1
- 229920001100 Polydextrose Polymers 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 244000191761 Sida cordifolia Species 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000034953 Twin anemia-polycythemia sequence Diseases 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 229960004892 acemetacin Drugs 0.000 description 1
- FSQKKOOTNAMONP-UHFFFAOYSA-N acemetacin Chemical compound CC1=C(CC(=O)OCC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 FSQKKOOTNAMONP-UHFFFAOYSA-N 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 1
- LNQVTSROQXJCDD-UHFFFAOYSA-N adenosine monophosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(CO)C(OP(O)(O)=O)C1O LNQVTSROQXJCDD-UHFFFAOYSA-N 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940023476 agar Drugs 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229960005142 alclofenac Drugs 0.000 description 1
- ARHWPKZXBHOEEE-UHFFFAOYSA-N alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000005157 alkyl carboxy group Chemical group 0.000 description 1
- 125000005189 alkyl hydroxy group Chemical group 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- JRTIDHTUMYMPRU-UHFFFAOYSA-N alpidem Chemical compound N1=C2C=CC(Cl)=CN2C(CC(=O)N(CCC)CCC)=C1C1=CC=C(Cl)C=C1 JRTIDHTUMYMPRU-UHFFFAOYSA-N 0.000 description 1
- 229950008673 alpidem Drugs 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001708 anti-dyslipidemic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 229940111133 antiinflammatory and antirheumatic drug oxicams Drugs 0.000 description 1
- 229940111131 antiinflammatory and antirheumatic product propionic acid derivative Drugs 0.000 description 1
- 229940125710 antiobesity agent Drugs 0.000 description 1
- 229940112930 apidra Drugs 0.000 description 1
- RCHHVVGSTHAVPF-ZPHPLDECSA-N apidra Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3N=CNC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CNC=N1 RCHHVVGSTHAVPF-ZPHPLDECSA-N 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 229960001671 azapropazone Drugs 0.000 description 1
- WOIIIUDZSOLAIW-NSHDSACASA-N azapropazone Chemical compound C1=C(C)C=C2N3C(=O)[C@H](CC=C)C(=O)N3C(N(C)C)=NC2=C1 WOIIIUDZSOLAIW-NSHDSACASA-N 0.000 description 1
- 229940092705 beclomethasone Drugs 0.000 description 1
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 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
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- IJTPQQVCKPZIMV-UHFFFAOYSA-N bucloxic acid Chemical compound ClC1=CC(C(=O)CCC(=O)O)=CC=C1C1CCCCC1 IJTPQQVCKPZIMV-UHFFFAOYSA-N 0.000 description 1
- 229950005608 bucloxic acid Drugs 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 230000003491 cAMP production Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 229960003184 carprofen Drugs 0.000 description 1
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 description 1
- 229940005991 chloric acid Drugs 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 125000002160 cholyl group Chemical group [H]C([H])([C@]1(C([C@@]2([H])O[H])([H])[H])[H])[C@@](O[H])([H])C([H])([H])C([H])([H])[C@]1(C([H])([H])[H])[C@]1([H])[C@]2([H])[C@]2([H])C([H])([H])C([H])([H])[C@@]([C@](C([H])([H])[H])(C(C(C(=O)[*])([H])[H])([H])[H])[H])([H])[C@@]2(C([H])([H])[H])[C@](O[H])([H])C1([H])[H] 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229950010886 clidanac Drugs 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 208000026758 coronary atherosclerosis Diseases 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- IRZVVDMCEZNNCW-UHFFFAOYSA-N cyclarbamate Chemical group C1CCCC1(COC(=O)NC=1C=CC=CC=1)COC(=O)NC1=CC=CC=C1 IRZVVDMCEZNNCW-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 229940009976 deoxycholate Drugs 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 229960003568 dexlansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-RUZDIDTESA-N dexlansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1C[S@@](=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-RUZDIDTESA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229960000616 diflunisal Drugs 0.000 description 1
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000000081 effect on glucose Effects 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229960004770 esomeprazole Drugs 0.000 description 1
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- ZWJINEZUASEZBH-UHFFFAOYSA-N fenamic acid Chemical class OC(=O)C1=CC=CC=C1NC1=CC=CC=C1 ZWJINEZUASEZBH-UHFFFAOYSA-N 0.000 description 1
- 229960001395 fenbufen Drugs 0.000 description 1
- ZPAKPRAICRBAOD-UHFFFAOYSA-N fenbufen Chemical compound C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 description 1
- IDKAXRLETRCXKS-UHFFFAOYSA-N fenclofenac Chemical compound OC(=O)CC1=CC=CC=C1OC1=CC=C(Cl)C=C1Cl IDKAXRLETRCXKS-UHFFFAOYSA-N 0.000 description 1
- 229950006236 fenclofenac Drugs 0.000 description 1
- 229950011481 fenclozic acid Drugs 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 229960002679 fentiazac Drugs 0.000 description 1
- 229960000489 feprazone Drugs 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 229950007979 flufenisal Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229960005051 fluostigmine Drugs 0.000 description 1
- 229950001284 fluprofen Drugs 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229950010931 furofenac Drugs 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000030135 gastric motility Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 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
- 239000003626 gastrointestinal polypeptide Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 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 1
- 230000010030 glucose lowering effect Effects 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229960004198 guanidine Drugs 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- WNRQPCUGRUFHED-DETKDSODSA-N humalog Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 WNRQPCUGRUFHED-DETKDSODSA-N 0.000 description 1
- 229940038661 humalog Drugs 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- CYWFCPPBTWOZSF-UHFFFAOYSA-N ibufenac Chemical compound CC(C)CC1=CC=C(CC(O)=O)C=C1 CYWFCPPBTWOZSF-UHFFFAOYSA-N 0.000 description 1
- 229950009183 ibufenac Drugs 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 150000005232 imidazopyridines Chemical class 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000012623 in vivo measurement Methods 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229960004187 indoprofen Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 108010050259 insulin degludec Proteins 0.000 description 1
- 108700039926 insulin glulisine Proteins 0.000 description 1
- 206010022498 insulinoma Diseases 0.000 description 1
- 229960004461 interferon beta-1a Drugs 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000006662 intracellular pathway Effects 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- QFGMXJOBTNZHEL-UHFFFAOYSA-N isoxepac Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CC(=O)O)=CC=C21 QFGMXJOBTNZHEL-UHFFFAOYSA-N 0.000 description 1
- 229950011455 isoxepac Drugs 0.000 description 1
- 229950002252 isoxicam Drugs 0.000 description 1
- YYUAYBYLJSNDCX-UHFFFAOYSA-N isoxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC=1C=C(C)ON=1 YYUAYBYLJSNDCX-UHFFFAOYSA-N 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 229940060975 lantus Drugs 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
- 229940102988 levemir Drugs 0.000 description 1
- UGOZVNFCFYTPAZ-IOXYNQHNSA-N levemir Chemical compound CCCCCCCCCCCCCC(=O)NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)CNC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2N=CNC=2)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=2N=CNC=2)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=2C=CC=CC=2)C(C)C)CSSC[C@@H]2NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)CSSC[C@H](NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC2=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H](CSSC1)C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=C(O)C=C1 UGOZVNFCFYTPAZ-IOXYNQHNSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229920001427 mPEG Polymers 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960003803 meclofenamic acid Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 1
- 229960004963 mesalazine Drugs 0.000 description 1
- IZXGZAJMDLJLMF-UHFFFAOYSA-N methylaminomethanol Chemical compound CNCO IZXGZAJMDLJLMF-UHFFFAOYSA-N 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 108010076432 minigastrin Proteins 0.000 description 1
- OJGQFYYLKNCIJD-UHFFFAOYSA-N miroprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1=CN(C=CC=C2)C2=N1 OJGQFYYLKNCIJD-UHFFFAOYSA-N 0.000 description 1
- 229950006616 miroprofen Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229960005285 mofebutazone Drugs 0.000 description 1
- REOJLIXKJWXUGB-UHFFFAOYSA-N mofebutazone Chemical compound O=C1C(CCCC)C(=O)NN1C1=CC=CC=C1 REOJLIXKJWXUGB-UHFFFAOYSA-N 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N mono-n-propyl amine Natural products CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- YRMLUAGKHYADKJ-UHFFFAOYSA-N necopidem Chemical compound C1=CC(CC)=CC=C1C1=C(CN(C)C(=O)CC(C)C)N2C=C(C)C=CC2=N1 YRMLUAGKHYADKJ-UHFFFAOYSA-N 0.000 description 1
- 229950002306 necopidem Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- BPGXUIVWLQTVLZ-OFGSCBOVSA-N neuropeptide y(npy) Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 BPGXUIVWLQTVLZ-OFGSCBOVSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960000916 niflumic acid Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- VOMXSOIBEJBQNF-UTTRGDHVSA-N novorapid Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 VOMXSOIBEJBQNF-UTTRGDHVSA-N 0.000 description 1
- 208000001797 obstructive sleep apnea Diseases 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- 229960001243 orlistat Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229960002739 oxaprozin Drugs 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229960000649 oxyphenbutazone Drugs 0.000 description 1
- HFHZKZSRXITVMK-UHFFFAOYSA-N oxyphenbutazone Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 HFHZKZSRXITVMK-UHFFFAOYSA-N 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000021255 pancreatic insulinoma Diseases 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000007180 physiological regulation Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229960000851 pirprofen Drugs 0.000 description 1
- PIDSZXPFGCURGN-UHFFFAOYSA-N pirprofen Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1N1CC=CC1 PIDSZXPFGCURGN-UHFFFAOYSA-N 0.000 description 1
- 230000007406 plaque accumulation Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 108010064470 polyaspartate Proteins 0.000 description 1
- 239000001259 polydextrose Substances 0.000 description 1
- 235000013856 polydextrose Nutrition 0.000 description 1
- 229940035035 polydextrose Drugs 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001289 polyvinyl ether Polymers 0.000 description 1
- 238000011176 pooling Methods 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960003101 pranoprofen Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 150000005599 propionic acid derivatives Chemical class 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 150000003248 quinolines Chemical group 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 231100000272 reduced body weight Toxicity 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- LIFDPEORUVTOCP-UHFFFAOYSA-N saripidem Chemical compound N1=C2C=CC=CN2C(CN(C)C(=O)CCC)=C1C1=CC=C(Cl)C=C1 LIFDPEORUVTOCP-UHFFFAOYSA-N 0.000 description 1
- 229950007359 saripidem Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229950005175 sudoxicam Drugs 0.000 description 1
- YHULXGUCQZFROV-UHFFFAOYSA-N sulfane;urea Chemical compound S.NC(N)=O YHULXGUCQZFROV-UHFFFAOYSA-N 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229960004492 suprofen Drugs 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 229940124598 therapeutic candidate Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 230000035922 thirst Effects 0.000 description 1
- 229960001312 tiaprofenic acid Drugs 0.000 description 1
- 229950002345 tiopinac Drugs 0.000 description 1
- 229950006150 tioxaprofen Drugs 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229960002905 tolfenamic acid Drugs 0.000 description 1
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229940007428 victoza Drugs 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 229950007802 zidometacin Drugs 0.000 description 1
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
- 229960003414 zomepirac Drugs 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- 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
- A61K38/2207—Gastrins; Cholecystokinins [CCK]
-
- 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
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
- A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
-
- 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
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- 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
- A61P3/06—Antihyperlipidemics
-
- 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
- A61P35/00—Antineoplastic agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
Abstract
本發明尤其關於某些肽結合物,及該等結合物用於治療多種疾病或病症(包括糖尿病(1型及/或2型)及糖尿病相關疾病或病症)之用途。
Description
本發明尤其係關於某些肽結合物,及該等結合物用於治療及/或預防多種疾病或病症(包括糖尿病(1型及/或2型)及糖尿病相關疾病或病症)之用途。
糖尿病(尤其是1型及2型糖尿病)連同肥胖症(咸信為2型糖尿病發展之主要致病因素)構成世界範圍內之主要且甚至是日益嚴重之健康問題。可能因糖尿病而發展之疾病或病症包括心血管及周邊血管疾病、微血管及大血管併發症、中風及可能某些形式之癌症。
糖尿病之特徵在於血糖含量之生理調節存在缺陷。可導致糖尿病之基礎條件為胰腺β-細胞質量及功能之減少或損失、內源性胰島素產生伴隨減少或損失及/或胰島素抗性(對胰島素之敏感性降低),亦即內源性胰島素對血糖含量之適當調節能力降低或損失。
許多降低血糖含量之激素響應腸內營養素之存在及吸收而由胃腸黏膜分泌。該等激素包括升糖素樣肽-1(GLP-1)、葡萄糖依賴性促胰島素肽(GIP)、胃泌素及胰泌素。
GLP-1[參見例如rskov,Diabetologia 35:701-711(1992)]由前升糖素(一種180個胺基酸之肽)之組織加工而產生[參見例如Drucker,Diabetes 47:159-169(1998)]。前升糖素之整個序列含有升糖素之29個胺基酸序列、GLP-1之36或37個胺基酸序列及升糖素樣肽-2(GLP-2;一種促腸
生長肽)之34個胺基酸序列。
所謂的腸促胰島素類似物(exendin)(構成另一組降低血糖含量之肽)與GLP-1(7-36)有一定序列類似性(53%)[參見例如Goke等人,J.Biol.Chem.268:19650-19655(1993)]。腸促胰島素類似物見於毒蜥科物種(珠蜥)之唾液中。腸促胰島素類似物-3存在於珠背毒蜥(Heloderma horridum)(墨西哥珠蜥(Mexican beaded lizard))之唾液中,而腸促胰島素類似物-4存在於短尾毒蜥(Heloderma suspectum)(鈍尾毒蜥(Gila monster))之唾液中。腸促胰島素類似物-4之胺基酸序列(在位置2及3處不同於腸促胰島素類似物-3之胺基酸序列)為HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2。
已報導,腸促胰島素類似物-4係一種對於經分離大鼠胰島素瘤細胞有效之GLP-1受體促效劑[Goke等人,loc.cit.]。WO 99/07404揭示全身投與之腸促胰島素類似物-4使得糖尿病db/db小鼠體內之血糖含量降低40%,且亦已報導每日一次腹膜內注射腸促胰島素類似物-4對糖尿病ob/ob小鼠之持久血糖降低作用[Grieg等人,Diabetologia 42:45-50(1999)]。
US 5,424,286及WO 98/05351揭示腸促胰島素類似物-3、腸促胰島素類似物-4及腸促胰島素類似物促效劑可用於治療糖尿病、用於減少胃運動及延遲胃排空且用於預防高血糖症,且WO 98/30231另外揭示其可用於減少食物攝取。
肽激素胃泌素係由胃黏膜內之細胞及十二指腸內之G細
胞分泌,且該激素對人類之主要生理學作用係刺激胃酸(亦即HCl)分泌且幫助胃運動。顯示胃泌素對小島新生發揮作用,亦即刺激胰島中分泌胰島素之β-細胞生長[參見例如Korc,M.,J.Clin.Invest.,92:1113-1114(1993);Rooman等人,Diabetes 51:686-690(2002)],且因此有助於調節血糖。
胃泌素與另一胃腸肽激素膽囊收縮素(CCK)共有受體。受體CCK-A R及CCK-B R對胃泌素及CCK變異體具有不同親和力。CCK-A R(或CCK R1)主要用作硫酸化CCK之受體,而CCK-B R(或CCK R2)同等結合CCK與胃泌素。CCK-B R由於胃泌素在血漿中與CCK相比之較高含量而被認為係「胃泌素受體」[Foucaud等人,Reg.Peptides 145:17-23(2008)]。
CCK-B R一旦發生配位體結合即可起始若干細胞內路徑,此被認為係CCK具有不同生理作用的原因。CCK-B R之關鍵路徑下游為MAPK(致裂物質活化蛋白激酶)或ERK(細胞外調節激酶)路徑,其亦由若干種生長激酶活化。由於CCK-B R在胰腺中表現,因此胃泌素能夠促成此組織中之細胞增殖及小島再生。
在人類中,胃泌素主要以三種形式出現,即胃泌素34、胃泌素17及胃泌素14(參考所關注序列中之胺基酸總數)。亦已識別胃泌素6。最短形式由C端醯胺化胃泌素34之裂解產生;因此胃泌素17由胃泌素34之最後17個C端殘基組成(對應於前胃泌素(55-71)),胃泌素14由胃泌素34之最後14
個C端殘基組成(對應於前胃泌素(58-71))且胃泌素6僅由胃泌素34之最後6個C端殘基組成(對應於前胃泌素(66-71))。在人類胃泌素17中,N端胺基酸殘基為焦麩胺酸(PyroGlu)殘基。經醯胺化之C端6胺基酸為胃泌素之關鍵受體結合殘基。
現已發現,包含兩個共價偶合或連接之肽部分的某些結合物與所關注之兩種個別肽之組合的治療活性相比,在治療例如糖尿病(1型及/或2型糖尿病)或各種其他糖尿病相關疾病或病症時可展示出乎意料之高治療活性。
在一個廣泛態樣中,本發明提供一種GLP-1受體促效劑與胃泌素(詳言之為在胃泌素17之位置15處(對應於胃泌素6之位置4)具有選自Leu、Nle、Phe及Thr之取代的胃泌素)之肽結合物。更特定而言,本發明提供腸促胰島素類似物-4與胃泌素之肽結合物。
在一些實施例中,本發明因此提供一種具有式I之肽結合物R1-Za-La-Ya-R2(I)其中R1為H、C1-4烷基、乙醯基、甲醯基、苄醯基或三氟乙醯基;R2為OH或NH2;且Za為具有式Ia之肽序列His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Z9-Leu-Ser-Z12-Z13-Z14-
Glu-Z16-Glu-Ala-Val-Z20-Leu-Phe-Ile-Z24-Z25-Leu-Z27-Z28(Ia)其中Z9係選自Asp及Glu;Z12係選自Lys、Arg及Orn;Z13係選自Gln及Tyr;Z14係選自Met及Leu;Z16係選自Glu、Cys、Arg、Orn及Lys;Z20係選自Arg、Lys及Orn;Z24係選自Lys、Arg、Orn及Glu;Z25係選自Trp、Lys、Cys及Phe;Z27係選自Lys、Arg及Orn;且Z28係選自Asn及Asp或不存在;La為具有式Ib之肽序列L1-L2-L3-L4(Ib)其中L1係選自Orn、8Ado、Cys、Lys及Gln或不存在;L2係選自Orn、8Ado、Cys、Lys及Gln或不存在;L3係選自Orn、8Ado、Cys、Lys及Gln或不存在;且L4係選自Orn、8Ado、Cys、Lys及Gln或不存在;且Ya為具有式Ic之肽序列:Y12-Y13-Y14-Y15-Asp-Y17(Ic)其中Y12係選自Tyr及Ala或不存在;
Y13係選自Gly及Ala或不存在;Y14係選自Trp、1Nal及Phe;Y15係選自Met、Leu、Nle、Thr及Phe;且Y17係選自Phe及3-(3-吡啶基)-丙胺酸;其中式Ia及Ib中之Lys、Orn或Cys中之至少一者進一步結合至親脂性及/或生物素基(biotinylic)取代基及/或經聚乙二醇化;或其醫藥學上可接受之鹽或溶劑合物。
在其他實施例中,本發明提供一種式I之肽結合物,其中Za為具有式IIa之肽序列His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Z9-Leu-Ser-Lys-Z13-Z14-Glu-Z16-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Z25-Leu-Lys-Z28(IIa)其中Z9係選自Glu及Asp;Z13係選自Gln及Tyr;Z14係選自Met及Leu;Z16係選自Glu、Cys及Lys;Z25係選自Lys、Phe、Cys及Trp;且Z28係選自Asn及Asp或不存在;La為如上所述具有式Ib之肽序列;且Ya為具有式IIc之肽序列Tyr-Gly-Trp-Y15-Asp-Phe(IIc)
其中Y15係選自Leu及Thr;且其中式IIa之位置Z16及Z25中之Lys殘基中之至少一者進一步結合至親脂性及/或生物素基取代基及/或經聚乙二醇化;或其醫藥學上可接受之鹽或溶劑合物。
在特定實施例中,本發明係關於一種具有下式之肽結合物:H-HGEGTFTSDLSKQLEEEAVRLFIEWLKN-8Ado-K(十六醯基-異Glu)-8Ado-YGWLDF-NH2(化合物1)H-HGEGTFTSDLSKQLEEEAVRLFIE-K(十六醯基-異Glu)-LKN-8Ado-8Ado-YGWLDF-NH2(化合物2)H-HGEGTFTSDLSKQLE-K(十六醯基-異Glu)-EAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2(化合物3)H-HGEGTFTSDLSKQMEEEAVRLFIEWLKN-8Ado-C(生物素-Mal)-8Ado-YGWLDF-NH2(化合物4)H-HGEGTFTSDLSKQLEEEAVRLFIE-C(生物素-Mal)-LKN-8Ado-8Ado-YGWLDF-NH2(化合物5)H-HGEGTFTSDLSKQLE-C(生物素-Mal)-EAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2(化合物6)H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-LK-8Ado-8Ado-YGWLDF-NH2(化合物7)H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-LK-8Ado-QQYGWLDF-NH2(化合物8)
或其醫藥學上可接受之鹽或溶劑合物。
在其他實施例中,本發明提供一種具有式III之肽結合物R1-Zb-Lb-Yb-R2(III)其中R1為H、C1-4烷基、乙醯基、甲醯基、苄醯基或三氟乙醯基;R2為OH或NH2;且Zb為具有式IIIa之肽序列His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Lys-Tyr-Leu-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Z25-Leu-Lys-Z28(IIIa)其中Z25係選自Phe及Trp;且Z28係選自Asn及Asp或不存在;Lb為具有式IIIb之肽序列L5-L6-L7-L8(IIIb)其中L5係選自8Ado、8Aoc、Ala、Gly及Gln或不存在;L6係選自8Ado、8Aoc、Ala、Gly及Gln或不存在;L7係選自8Ado、8Aoc、Ala、Gly及Gln或不存在;且L8係選自8Ado、8Aoc、Ala、Gly及Gln或不存在;且Yb為具有式IIIc之肽序列Y10-Y11-Tyr-Gly-Trp-Y15-Asp-Phe(IIIc)其中
Y10為Glu或不存在;Y11為Ala或不存在;且Y15係選自Leu及Thr;或其醫藥學上可接受之鹽或溶劑合物;其限制條件為式III不為H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Ado-8Ado-YGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLKYGWLDF-NH2;及H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Ado-YGWLDF-NH2。
在其他實施例中,本發明提供一種式III之肽結合物,其中Zb為具有式IVa之肽序列His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Lys-Tyr-Leu-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Z25-Leu-Lys-Asn(IVa)其中Z25係選自Lys、Phe及Trp;且Lb為如上所述具有式IIIb之肽序列;Yb為具有式IVc之肽序列Tyr-Gly-Trp-Y15-Asp-Phe(IVc)其中Y15係選自Leu及Thr;
或其醫藥學上可接受之鹽或溶劑合物。
在特定實施例中,本發明係關於一種具有下式之肽結合物:H-HGEGTFTSELSKYLEEEAVRLFIEFLKQQYGWLDF-NH2(化合物9)H-HGEGTFTSELSKYLEEEAVRLFIEFLKQQEAYGWLDF-NH2(化合物10)H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Ado-QQYGWLDF-NH2(化合物11)H-HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWLDF-NH2(化合物12)H-HGEGTFTSELSKYLEEEAVRLFIEFLKAAAYGWLDF-NH2(化合物13)H-HGEGTFTSELSKYLEEEAVRLFIEFLKGGGYGWLDF-NH2(化合物14)H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Aoc-YGWLDF-NH2(化合物15)H-HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWLDF-NH2(化合物16)H-HGEGTFTSELSKYLEEEAVRLFIEFLKAYGWLDF-NH2(化合物17)H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-8Ado-8Ado-YGWLDF-NH2(化合物18)H-HGEGTFTSELSKYLEEEAVRLFIEFLKD-8Ado-8Ado-
YGWLDF-NH2(化合物19)H-HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWTDF-NH2(化合物20)H-HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWTDF-NH2(化合物21)H-HGEGTFTSELSKYLEEEAVRLFIEWLKNYGWLDF-NH2(化合物22)H-HGEGTFTSELSKYLEEEAVRLFIEWLKDYGWLDF-NH2(化合物23)或其醫藥學上可接受之鹽或溶劑合物。
在特定實施例中,本發明之肽結合物可藉由標準合成方法,藉由使用重組表現系統或藉由任何其他適合方法來製造。因此,結合物可由多種方式來合成,例如包括包含以下之方法:(a)藉由標準固相或液相方法逐步或藉由片段組裝合成肽結合物,並分離及純化最終肽結合物產物;(b)在宿主細胞中表現編碼肽結合物之核酸構築體且自宿主細胞培養物回收表現產物;或(c)實現編碼肽結合物之核酸構築體的無細胞活體外表現,且回收表現產物;或藉由方法(a)、(b)或(c)之任意組合獲得肽結合物之片段,隨後接合該等片段以獲得肽結合物,且回收肽結合物。
本發明之其他實施例為治療多種病狀、疾病或病症(包
括糖尿病(1型及2型)及各種糖尿病相關病狀、疾病或病症)之方法。該等實施例包含投與本發明之肽結合物(游離形式或其醫藥學上可接受之鹽或溶劑合物形式)以及包含本發明之肽結合物或其醫藥學上可接受之鹽或溶劑合物的醫藥組合物。
在一些實施例中,本發明之肽結合物可適用作用於治療以下疾病之醫藥劑:胰島素抗性、葡萄糖耐受不良、糖尿病前期、代謝症候群、空腹葡萄糖含量升高、與血糖含量升高相關之疾病病況、高血糖症、1型及/或2型糖尿病、糖尿病性神經病、糖尿病性視網膜病、糖尿病性腎病變、腎衰竭、高血壓及/或血脂異常(或該等代謝與心血管風險因素之組合)、動脈粥樣硬化、動脈硬化、大血管疾病、微血管疾病、冠心病、周邊動脈疾病及中風。其亦可適用於預防體重增加、促進體重減輕、減少過重體重及/或治療肥胖(例如藉由控制食慾、進食、食物攝取、熱量攝取及/或能量消耗),包括病態肥胖以及相關疾病、病症及健康病狀,包括(但不限於)肥胖相關炎症、肥胖相關膽囊疾病及肥胖誘發之睡眠呼吸暫停。本發明之肽結合物對該等病狀之作用可經由對體重之作用而整體或部分調節,或可不依賴於其。
本發明之其他實施例為預防多種病狀、疾病或病症(包括糖尿病(1型及2型)及各種糖尿病相關病狀、疾病或病症)之方法。該等實施例包含投與本發明之肽結合物(游離形式或其醫藥學上可接受之鹽或溶劑合物形式)以及包含本
發明之肽結合物或其醫藥學上可接受之鹽或溶劑合物的醫藥組合物。
在一些實施例中,本發明之肽結合物可適用作用於預防以下疾病之醫藥劑:胰島素抗性、葡萄糖耐受不良、糖尿病前期、代謝症候群、空腹葡萄糖含量升高、與血糖含量升高相關之疾病病況、高血糖症、1型及/或2型糖尿病、糖尿病性神經病、糖尿病性視網膜病、糖尿病性腎病變、腎衰竭、高血壓及/或血脂異常(或該等代謝與心血管風險因素之組合)、動脈粥樣硬化、動脈硬化、大血管疾病、微血管疾病、冠心病、周邊動脈疾病及中風。其亦可適用於預防體重增加、促進體重減輕、減少過重體重及/或治療肥胖(例如藉由控制食慾、進食、食物攝取、熱量攝取及/或能量消耗),包括病態肥胖以及相關疾病、病症及健康病狀,包括(但不限於)肥胖相關炎症、肥胖相關膽囊疾病及肥胖誘發之睡眠呼吸暫停。本發明之肽結合物對該等病狀之作用可經由對體重之作用而整體或部分調節,或可不依賴於其。
本發明之其他態樣將由以下揭示內容知曉。
如上文所示,本發明之一個態樣係關於一種具有下式之肽結合物:H-HGEGTFTSDLSKQLEEEAVRLFIEWLKN-8Ado-K(十六醯基-異Glu)-8Ado-YGWLDF-NH2(化合物1)H-HGEGTFTSDLSKQLEEEAVRLFIE-K(十六醯基-異Glu)-
LKN-8Ado-8Ado-YGWLDF-NH2(化合物2)H-HGEGTFTSDLSKQLE-K(十六醯基-異Glu)-EAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2(化合物3)H-HGEGTFTSDLSKQMEEEAVRLFIEWLKN-8Ado-C(生物素-Mal)-8Ado-YGWLDF-NH2(化合物4)H-HGEGTFTSDLSKQLEEEAVRLFIE-C(生物素-Mal)-LKN-8Ado-8Ado-YGWLDF-NH2(化合物5)H-HGEGTFTSDLSKQLE-C(生物素-Mal)-EAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2(化合物6)H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-LK-8Ado-8Ado-YGWLDF-NH2(化合物7)H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-LK-8Ado-QQYGWLDF-NH2(化合物8)。
此外,在另一態樣中,本發明係關於一種具有下式之肽結合物:H-HGEGTFTSELSKYLEEEAVRLFIEFLKQQYGWLDF-NH2(化合物9)H-HGEGTFTSELSKYLEEEAVRLFIEFLKQQEAYGWLDF-NH2(化合物10)H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Ado-QQYGWLDF-NH2(化合物11)H-HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWLDF-NH2(化合物12)H-HGEGTFTSELSKYLEEEAVRLFIEFLKAAAYGWLDF-
NH2(化合物13)H-HGEGTFTSELSKYLEEEAVRLFIEFLKGGGYGWLDF-NH2(化合物14)H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Aoc-YGWLDF-NH2(化合物15)H-HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWLDF-NH2(化合物16)H-HGEGTFTSELSKYLEEEAVRLFIEFLKAYGWLDF-NH2(化合物17)H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-8Ado-8Ado-YGWLDF-NH2(化合物18)H-HGEGTFTSELSKYLEEEAVRLFIEFLKD-8Ado-8Ado-YGWLDF-NH2(化合物19)H-HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWTDF-NH2(化合物20)H-HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWTDF-NH2(化合物21)H-HGEGTFTSELSKYLEEEAVRLFIEWLKNYGWLDF-NH2(化合物22)H-HGEGTFTSELSKYLEEEAVRLFIEWLKDYGWLDF-NH2(化合物23)H-HGEGTFTSELSKYLEEEAVRLFIEFLKEAYGWLDF-NH2(化合物24)。
在又一態樣中,本發明係關於一種具有下式之肽結合
物:H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-K(十六醯基-異Glu)-YGWLDF-NH2(化合物25)H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-K(十六醯基-異Glu)-WLDF-NH2(化合物26)H-HGEGTFTSELSKYLE-K(十六醯基-異Glu)-EAVRLFIEFLKNYGWLDF-NH2(化合物27)H-HGEGTFTSELSKYLE-K(十六醯基-異Glu)-EAVRLFIEFLKNWLDF-NH2(化合物28)H-HGEGTFTSELSKYLEEEAVRLFIEFLK-K(十六醯基-異Glu)-YGWLDF-NH2(化合物29)H-HGEGTFTSELSKYLEEEAVRLFIEFLK-K(十六醯基-異Glu)-WLDF-NH2(化合物30)H-HGEGTFTSELSKYLE-K(十六醯基-異Glu)-EAVRLFIEFLKYGWLDF-NH2(化合物31)H-HGEGTFTSELSKYLE-K(十六醯基-異Glu)-EAVRLFIEFLKWLDF-NH2(化合物32)H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-LK-8Ado-YGWLDF-NH2(化合物33)H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-LKQQYGWLDF-NH2(化合物34)H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-LK-Orn-Orn-YGWLDF-NH2(化合物35)H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-
LKNYGWLDF-NH2(化合物36)H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-LKDYGWLDF-NH2(化合物37)。
在另一態樣中,本發明係關於一種具有下式之肽結合物:H-HGEGTFTSDLSKQLEEEAVRLFIEC(PEG5K)LKN-8Ado-8Ado-YGWLDF-NH2(化合物38)H-HGEGTFTSELSKYLEEEAVRLFIEC(PEG10K)LK-8Ado-8Ado-YGWLDF-NH2(化合物39)H-HGEGTFTSELSKYLEEEAVRLFIEC(PEG20K)LK-8Ado-8Ado-YGWLDF-NH2(化合物40)H-HGEGTFTSELSKYLEEEAVRLFIEC(PEG40K)LK-8Ado-8Ado-YGWLDF-NH2(化合物41)H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNYGWTDF-OH(化合物42)H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-8Ado-8Ado-YGWTDF-NH2(化合物43)或其醫藥學上可接受之鹽或溶劑合物。
縮寫8Ado、8Aoc、十六醯基、異Glu、Orn及生物素-Mal分別表示以下非天然產生之胺基酸部分:8Ado(或Peg3):-NH-CH2-CH2-O-CH2-CH2-O-CH2-C(O)-(衍生自8-胺基-3,6-二氧雜辛酸);8Aoc:-NH-CH2-CH2-CH2-CH2-CH2-CH2-CH2-C(O)-(衍生自8-胺基辛酸);
十六醯基:CH3-(CH2)14-C(O)-;異Glu:-NH-CH(COOH)-CH2-CH2-C(O)-;Orn:鳥胺酸;且生物素-Mal:生物素-順丁烯二醯亞胺。
關於本發明肽結合物中連接子部分之定向,連接子部分-8Ado-8Ado-例如表示化學部分-NH-CH2-CH2-O-CH2-CH2-O-CH2-C(O)-NH-CH2-CH2-O-CH2-CH2-O-CH2-C(O)-,位於所關注連接子部分末端之-NH-....部分共價連接至所關注肽結合物之GLP-1促效劑(例如腸促胰島素類似物-4衍生)部分,且位於所關注連接子部分右側之....-C(O)-部分連接至所關注肽結合物之胃泌素衍生部分。
在上文所列之本發明肽結合物中,應瞭解,腸促胰島素類似物-4(1-28)肽序列部分衍生自短尾毒蜥腸促胰島素類似物-4序列之序列或為其類似物。
本發明上下文中之術語「腸促胰島素類似物-4類似物」被定義為衍生自原生腸促胰島素類似物-4序列之任何取代、截短、缺失、添加或結合之肽序列。此包括(但不限於)本發明之取代。
同樣,結合物中之[Leu4]胃泌素6部分以合成方式衍生自人類胃泌素。
亦同樣,結合物中之[Leu15]胃泌素17部分以合成方式衍生自人類胃泌素。
每一上述肽結合物1-41個別地(亦即化合物1或化合物2
或化合物3...等等,直至化合物41)或其醫藥學上可接受之鹽或溶劑合物構成本發明之另一個別態樣。
在本發明上下文中,除非胺基酸以其全名提及(例如丙胺酸、精胺酸等),否則其由其習知三個字母及/或單一字母縮寫表示(例如Ala或A表示丙胺酸、Arg或R表示精胺酸等)。
本發明上下文中之術語「肽結合物」係指第一肽部分直接或經由藉助於共價化學鍵結鍵聯(亦即橋接或間隔)化學部分而與第二肽部分連接(亦即偶合或鍵聯)的分子。
在本發明之肽結合物中,腸促胰島素類似物-4或Z(Za或Zb)與原生短尾毒蜥腸促胰島素類似物-4可具有至少75%一致性,例如至少80%、85%、90%、95%、96%、97%、98%、99%或100%一致性。
在本發明之肽結合物中,胃泌素或Y(Ya或Yb)與原生人類胃泌素17及/或胃泌素6可具有至少70%一致性,例如當可能時至少75%、80%、83%、85%、90%、94%、95%、96%、97%、98%、99%或100%一致性。
在一些實施例中,本發明之多肽可包含以下編號化合物之任一者中所列之胺基酸序列:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40及41或可能時其與一或多個引用序列具有至少約80%、85%、90%、95%、97%、98%、99%或99.5%一致性之功能性片段或變異體。胺基酸
取代可為例如保守取代。
如本文所用之術語「保守取代」表示一或多個胺基酸由另一生物學類似殘基置換。實例包括具有類似特徵之胺基酸殘基的取代,例如小胺基酸、酸性胺基酸、極性胺基酸、鹼性胺基酸、疏水性胺基酸及芳族胺基酸。舉例而言,在本發明之一個較佳實施例中,Met殘基經正白胺酸(Nle)取代,Nle對於Met而言為生物電子等排物體,但與Met相反不易於氧化。以通常不見於內源性哺乳動物肽及蛋白質中之殘基進行的保守取代之另一實例為以例如鳥胺酸、刀豆胺酸、胺基乙基半胱胺酸或其他鹼性胺基酸保守取代Arg或Lys。關於肽及蛋白質中之表現型靜止取代的其他資訊參見例如Bowie等人,Science 247,1306-1310,1990。胺基酸之保守取代由物理化學性質來分組。I:中性、親水性,II:酸及醯胺,III:鹼性,IV:疏水性,V:芳族、龐大胺基酸。
在一些實施例中,本發明之多肽可包含其功能片段或變異體,其與一或多個所述序列相比具有至多20、15、10、9、8、7、6、5、4、3、2或1個胺基酸取代。本發明之多肽可另外具有或不具有信號序列。
在一些實施例中,本發明多肽之一或多個半胱胺酸可由
其他殘基(諸如絲胺酸)取代。
在一些實施例中,本發明之多肽與以下編號化合物中之任一者共有至少99%之胺基酸序列一致性:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40及41。
本發明中之術語「醫藥學上可接受之鹽」(本發明肽結合物之醫藥學上可接受之鹽)欲表示對所關注鹽投與之患者或個體無害之鹽。其可適合地為例如選自酸加成鹽及鹼鹽之鹽。酸加成鹽之實例包括氯化物鹽、檸檬酸鹽及乙酸鹽。鹼鹽之實例包括陽離子選自鹼金屬陽離子(諸如鈉或鉀離子)、鹼土金屬陽離子(諸如鈣或鎂離子)以及經取代銨離子(諸如N(R1)(R2)(R3)(R4)+型離子,其中R1、R2、R3及R4一般將獨立地表示氫、視情況經取代之C1-6烷基或視情況經取代之C2-6烯基)之鹽。相關C1-6烷基之實例包括甲基、乙基、1-丙基及2-丙基。可能相關之C2-6烯基之實例包括乙烯基、1-丙烯基及2-丙烯基。醫藥學上可接受之鹽之其他實例述於「Remington's Pharmaceutical Sciences」,第17版,Alfonso R.Gennaro(編),Mark Publishing Company,Easton,PA,USA,1985(及其最近版本)、「Encyclopaedia of Pharmaceutical Technology」,第3版,James Swarbrick(編),Informa Healthcare USA(Inc.),NY,USA,2007及J.Pharm.Sci.66:2(1977)中。
本發明中之術語「溶劑合物」係指在溶質(在此情形下
為本發明之肽結合物或其醫藥學上可接受之鹽)與溶劑之間形成的具有指定化學計量之複合物。此溶劑可為例如水、乙醇,或另一醫藥學上可接受之一般小分子的有機物質,諸如(但不限於)乙酸或乳酸。當所關注溶劑為水時,該溶劑合物通常稱為水合物。
本發明之一些實施例係關於本發明之肽結合物或其醫藥學上可接受之鹽用作藥劑或用於製造或製備藥劑,或係關於肽結合物或其醫藥學上可接受之鹽於治療或預防多種疾病或病狀之用途,該等疾病或病狀為例如:
1型糖尿病、2型糖尿病、糖尿病前期、胰島素抗性症候群、葡萄糖耐受性異常(IGT)、與血糖含量升高相關之疾病病況、高血糖症、高血壓、致動脈粥樣硬化性血脂異常、動脈硬化(例如動脈粥樣硬化)、大血管疾病、冠心病、周邊動脈疾病、中風、微血管疾病、胃病、代謝症候群、癌症(例如結腸癌)、發炎性腸病(IBD)、大腸急躁症(IBS)、糖尿病性神經病、糖尿病性視網膜病、糖尿病性腎病變及腎衰竭。
可能與此相關之其他疾病或病症包括肥胖、病態肥胖、肥胖相關炎症、肥胖相關膽囊病及肥胖誘發之睡眠呼吸暫停。
在一些實施例中,本發明之藥劑為用於治療有此需要之個體的藥劑。
在其他實施例中,本發明之藥劑為用於在有此需要之個體體內誘發胰島新生(例如用於促進胰島中形成新β-細胞)的藥劑。
在其他實施例中,本發明之藥劑為用於在有此需要之個體體內誘發胰島中之β-細胞存活(例如用於預防胰島中之β-細胞損失)的藥劑。
在其他實施例中,本發明之藥劑為用於在有此需要之個體體內誘發胰島中之β-細胞增殖(例如用於促進胰島中之現有β-細胞增殖)的藥劑。
在其他實施例中,本發明之藥劑為用於在有此需要之個體體內誘發以上提及過程之任意組合(亦即胰島新生、胰島中之β-細胞存活及/或胰島中之β-細胞增殖)的藥劑。
根據實施例技術方案39之肽結合物或其醫藥學上可接受之鹽或溶劑合物之用途,其中該藥劑係用於改善有此需要之個體體內之胰島β-細胞的存活率。
在其他實施例中,本發明之藥劑為用於在有此需要之個體體內預防胰島中之β-細胞凋亡及/或壞死(例如用於預防胰島中之β-細胞損失)的藥劑。
在其他實施例中,本發明之藥劑為用於在有此需要之個體體內降低血液中之血紅素b1Ac(糖基化血紅素;HbA1c)含量之藥劑。
本發明之另一態樣係關於本發明之肽結合物在製造或製備用於在有此需要之個體中治療一或多種本文所揭示之病狀之藥劑中的用途。
本發明之肽結合物可進一步用於:製造用於在有此需要之個體體內誘發胰島新生之藥劑;製造用於在有此需要之個體體內預防胰島中之β-細胞凋亡
之藥劑;製造用於在有此需要之個體體內誘發胰島中之β-細胞存活之藥劑;製造用於在有此需要之個體體內誘發胰腺β-細胞增殖之藥劑;製造用於降低有此需要之個體的血液中之血紅素b1Ac(糖基化血紅素;HbA1c)含量之藥劑;及/或其任何組合。
本發明之相關其他態樣為治療本文所揭示之病狀、疾病或病症之相應方法。因此,本發明之一個該種額外態樣係關於一種在有此需要之個體中治療一或多種本文所揭示之疾病、病症或病狀之方法,該方法包含向個體投與治療有效量之本發明之肽結合物或其醫藥學上可接受之鹽或溶劑合物。
本發明之其他實施例係關於一種用於在有此需要之個體體內誘發胰島新生之方法,該方法包含向個體投與治療有效量之本發明之肽結合物或其醫藥學上可接受之鹽或溶劑合物。
本發明之其他實施例係關於一種在有此需要之個體體內促進胰島中之β-細胞存活之方法,該方法包含向個體投與治療有效量之本發明之肽結合物或其醫藥學上可接受之鹽或溶劑合物。
本發明之其他實施例係關於一種用於在有此需要之個體體內減少或預防胰島中之β-細胞凋亡及/或壞死之方法,該
方法包含向個體投與治療有效量之本發明之肽結合物或其醫藥學上可接受之鹽或溶劑合物。
本發明之其他實施例係關於一種用於在有此需要之個體體內誘發胰島中之β-細胞增殖之方法,該方法包含向個體投與治療有效量之本發明之肽結合物或其醫藥學上可接受之鹽或溶劑合物。
本發明之其他實施例係關於一種用於在有此需要之個體體內誘發上文提及過程之任何組合(亦即胰島新生、胰島中之β-細胞存活及/或胰島中之β-細胞增殖)之方法,該方法包含向個體投與治療有效量之本發明之肽結合物或其醫藥學上可接受之鹽或溶劑合物。
本發明之其他實施例係關於一種用於降低有此需要之個體的血液中之血紅素b1Ac(糖基化血紅素;HbA1c)含量之方法,該方法包含向個體投與治療有效量之本發明之肽結合物或其醫藥學上可接受之鹽或溶劑合物。
本發明之其他實施例係關於以下:一種在有此需要之個體中治療與血糖含量升高相關之疾病病況的方法;一種在有此需要之個體中降低血糖含量之方法;一種在有此需要之個體中刺激胰島素釋放之方法;一種在有此需要之個體中調節胃排空之方法;及一種在有此需要之個體中降低血漿脂質含量之方法;一種降低有此需要之個體之血壓的方法;一種減輕有此需要之個體之體重的方法。
在本發明之每一後續方法中,該方法包含向個體投與治療有效量之本發明之肽結合物或其醫藥學上可接受之鹽或溶劑合物。
如本發明之上述治療方法或其他治療性干預之情形下所採用之術語「治療有效量」係指例如由確定臨床終點或其他生物標記(確定生物標記或實驗生物標記)所量測的足以治癒、改善、緩解或部分阻止作為所關注治療或其他治療性干預之目標之特定疾病、病症或病狀之臨床表現的量。治療相關量可基於待治療或預防之適應症及治療相關量所投與之個體由熟習此項技術者憑經驗確定。舉例而言,熟練操作者可量測具有本文所述生物活性之一或多個臨床相關指示,例如血糖含量、胰島素釋放及血漿脂質含量。熟練操作者可經由活體外或活體內量測確定臨床相關量。其他例示性量度包括體重增加、體重減輕及血壓變化。
足夠達成任何或所有該等作用之量被定義為治療有效量。可調節投藥量及投藥方法來達成最佳功效。對於指定目的有效之量將尤其取決於作為特定治療或其他治療性干預之目標之疾病、病症或病狀之嚴重度、所關注個體之體重及一般狀況、飲食、可能併用之藥物及熟習醫學技術者熟知之其他因素。最適合向人類投與本發明之肽結合物或其醫藥學上可接受之鹽或溶劑合物之適當劑量大小及給藥方案的確定可由本發明獲得之結果來指導,且可由適當設計之臨床試驗來證實。有效劑量及治療方案可由習知方式確定,在實驗室動物中由低劑量開始且隨後增加劑量,同
時監測效應,且亦系統地改變給藥方案。臨床醫師在確定用於指定個體之最佳劑量時可考慮許多因素。該等考慮因素為熟習此項技術者所熟知。
如本文明上下文所採用之術語「治療(treatment)」及語法變化形式(例如「治療(treated)」、「治療(treating)」、「治療(treat)」)係指一種獲得有益或所需臨床結果之方式。在本發明中,有益或所需臨床結果包括(但不限於)症狀緩解、疾病程度降低、疾病病況穩定(亦即不惡化)、疾病進展延遲或減緩、疾病病況改善或緩和及緩解(部分或總體),而無論可偵測抑或不可偵測。「治療」亦可意謂若未接受治療,則相對於預期存活時間延長存活。需要治療之個體(例如人類)因此可為已罹患所關注疾病或病症之個體。術語「治療」包括相對於不存在治療之情況抑制或減少病理狀況或症狀(例如體重增加或高血糖症)之嚴重度的增加,且不一定意謂表示相關疾病、病症或病狀之完全中止。
如本文明上下文所採用之術語「預防(preventing)」及其語法變化形式(例如「預防(prevented)」、「預防(preventing)」、「預防(prevent)」係指一種預防病狀、疾病或病症發展或改變其病理狀況之方式。因此,「預防(prevention)」可指防止性或預防性措施。在本發明中,有益或所需臨床結果包括(但不限於)預防或減緩疾病之症狀、進程或發展,而無論可偵測抑或不可偵測。需要預防之個體(例如人類)因此可為尚未罹患所關注疾病或病症之
個體。術語「預防」因此包括相對於不存在治療之情況減緩疾病發作,且不一定意謂表示相關疾病、病症或病狀之永久預防。
如本文明上下文所採用之術語「促效劑」係指使所關注受體類型活化之物質(配位體)。
如本文明上下文所採用之術語「GLP-1受體促效劑」(有時在別處稱作「GLP-1促效劑」)係指使GLP-1受體(諸如人類GLP-1受體)活化之物質(配位體)。使人類GLP-1受體活化之物質包括原生GLP-1肽激素GLP-1(7-37)、GLP-1(7-36)醯胺、調酸素、腸促胰島素類似物-3、腸促胰島素類似物-4、升糖素、胃抑制多肽(GIP)及其功能性肽類似物及衍生物。
如本文明上下文所採用之術語「拮抗劑」係指阻斷、中和或抵消充當促效劑之另一物質(配位體)對所關注受體類型之作用的物質(配位體)。
在本發明之一些實施例中,聯繫上述本發明之各種態樣而提及之需要特定治療或其他治療性干預之個體為哺乳動物。在其他實施例中,該哺乳動物為人類。
本發明之其他實施例係關於包含本發明之肽結合物或其醫藥學上可接受之鹽或溶劑合物連同醫藥學上可接受之載劑、賦形劑或媒劑之醫藥組合物。
本發明之肽結合物可藉由標準合成方法,藉由使用重組表現系統或藉由任何其他適合方法來製造。因此,結合物
可由多種方式來合成,例如包括包含以下之方法:(a)藉由標準固相或液相方法逐步或藉由片段組裝合成肽結合物,且分離並純化最終肽結合物產物;(b)在宿主細胞中表現編碼肽結合物之核酸構築體且自宿主細胞培養物回收表現產物;或(c)實現編碼肽結合物之核酸構築體的無細胞活體外表現,且回收表現產物;或藉由方法(a)、(b)或(c)之任意組合獲得肽結合物之片段,隨後接合該等片段以獲得肽結合物,且回收肽結合物。
較佳藉由固相或液相肽合成來合成本發明之結合物。在本文中,可參考WO 98/11125或尤其參考Fields,G.B.等人,「Principles and Practice of Solid-Phase Peptide Synthesis」;Synthetic Peptides,Gregory A.Grant(編),Oxford University Press(第2版,2002)及其中之合成實例。
本發明化合物中之一或多個胺基酸側鏈可進一步結合至親脂性取代基。親脂性取代基可與胺基酸側鏈中之原子共價鍵結,或者可由間隔子結合至胺基酸側鏈。胺基酸可為肽Z之一部分或肽L之一部分。
不希望受理論束縛,認為親脂性取代基結合血流中之白蛋白,因此使本發明化合物免於酶降解,由此可延長化合物之半衰期。間隔子(存在時)可在化合物與親脂性取代基之間提供間隔。
親脂性取代基可經由酯、磺醯基酯、硫酯、醯胺或磺醯胺連接至胺基酸側鏈或間隔子。因此,應瞭解,在一些實施例中,親脂性取代基包括醯基、磺醯基、N原子、O原子或S原子,其形成酯、磺醯基酯、硫酯、醯胺或磺醯胺之部分。親脂性取代基中之醯基較佳形成具有胺基酸側鏈或間隔子之醯胺或酯之部分。
親脂性取代基可包括具有4至30個C原子、例如至少8或12個C原子且較佳24個或24個以下C原子或20個或20個以下C原子之烴鏈。該烴鏈可為直鏈或分支鏈且可為飽和或不飽和的。應瞭解,烴鏈較佳經形成與胺基酸側鏈或間隔子連接之部分的部分(例如醯基、磺醯基、N原子、O原子或S原子)取代。烴鏈最佳經醯基取代,且因此烴鏈可為烷醯基之部分,例如軟脂醯基、己醯基、月桂醯基、肉豆蔻醯基或硬脂醯基。
因此,親脂性取代基可具有下文所示之式:
A可為例如醯基、磺醯基、NH、N-烷基、O原子或S原子,較佳為醯基。n為3至29之整數。在一些實施例中,n為至少7或至少11。在一些實施例中,n為23或23以下。在一些實施例中,n為19或19以下。
烴鏈可經進一步取代。舉例而言,其可經至多三個選自NH2、OH及COOH之取代基進一步取代。若烴鏈經進一步取代,則其較佳僅經一個取代基進一步取代。或者或另
外,烴鏈可包括環烷烴或雜環烷烴,例如如下文所示:
在一些實施例中,環烷烴或雜環烷烴為六員環。在某些較佳實施例中,其為哌啶。
或者,親脂性取代基可基於環戊菲骨架,其可為部分或完全不飽和或飽和。骨架中之碳原子各自可經Me或OH取代。舉例而言,親脂性取代基可為膽酸基(cholyl)、去氧膽酸基或石膽酸基。
如上所示,親脂性取代基可由間隔子與胺基酸側鏈結合。存在時,間隔子連接至親脂性取代基且連接至胺基酸側鏈。間隔子可藉由酯、磺醯基酯、硫酯、醯胺或磺醯胺獨立地連接至親脂性取代基且連接至胺基酸側鏈。因此,其可包括兩個獨立地選自醯基、磺醯基、N原子、O原子或S原子之部分。間隔子可具有下式:
其中B與D各自獨立地選自醯基、磺醯基、NH、N-烷基、O原子或S原子,較佳選自醯基及NH。n較佳為1至10、例如1至5之整數。間隔子可視情況經一或多個選自C1-6烷基、C1-6烷基胺、C1-6烷基羥基及C1-6烷基羧基之取代基進一步取代。
或者,間隔子可具有兩個或兩個以上上式之重複單元。對於每一重複單元而言,B、D及n各自獨立地選擇。相鄰
重複單元可經由其各自之B及D部分彼此共價連接。舉例而言,相鄰重複單元之B及D部分可一起形成酯、磺醯基酯、硫酯、醯胺或磺醯胺。每一間隔子末端處之自由B及D單元連接至如上所述之胺基酸側鏈及親脂性取代基。
間隔子較佳具有5個或5個以下、4個或4個以下或3個或3個以下重複單元。間隔子最佳具有兩個重複單元或為單一單元。
間隔子(或若間隔子具有重複單元,則為一或多個間隔子重複單元)可為例如天然或非天然胺基酸。應瞭解,對於具有官能化側鏈之胺基酸而言,B及/或D可為胺基酸側鏈內之部分。間隔子可為任何天然產生或非天然之胺基酸。舉例而言,間隔子(或若間隔子具有重複單元,則為一或多個間隔子重複單元)可為Gly、Pro、Ala、Val、Leu、Ile、Met、Cys、Phe、Tyr、Trp、His、Lys、Arg、Gln、Asn、α-Glu、γ-Glu、Asp、Ser、Thr、Gaba、Aib、bAla、5-胺基戊醯基、6-胺基己醯基、7-胺基庚醯基、8-胺基辛醯基、9-胺基壬醯基或10-胺基癸醯基。
舉例而言,間隔子可為選自γ-Glu、Gaba、b-Ala及α-Gly之單一胺基酸。
親脂性取代基可結合至本發明化合物中之任何胺基酸側鏈。胺基酸側鏈較佳包括羧基、羥基、硫醇、醯胺或胺基,以供與間隔子或親脂性取代基形成酯、磺醯基酯、硫酯、醯胺或磺醯胺。舉例而言,親脂性取代基可結合至Asn、Asp、Glu、Gln、His、Lys、Arg、Ser、Thr、Tyr、
Trp、Cys或Dbu、Dpr或Orn。親脂性取代基較佳結合至Lys或Cys。然而,如本文所提供之各式中以Lys表示之任何胺基酸在添加親脂性取代基時均可由Dbu、Dpr或Orn置換。
親脂性取代基及間隔子之實例在下式中展示:
此處,來自本發明化合物(例如來自X)之Lys經由醯胺部分與γ-Glu(間隔子)共價連接。軟脂醯基經由醯胺部分與γ-Glu間隔子共價連接。
或者或另外,本發明化合物中之一或多個胺基酸側鏈可進一步結合至生物素基取代基。生物素基取代基可與胺基酸側鏈中之原子共價鍵結,或者可由間隔子結合至胺基酸側鏈。胺基酸可為肽Z之一部分或肽L之一部分。
不希望受理論束縛,認為生物素基取代基結合血流中之白蛋白,因此使本發明化合物免於酶降解,由此可延長化合物之半衰期。間隔子(存在時)可用於在化合物與生物素基取代基之間提供間隔。
生物素基取代基可經由順丁烯二醯亞胺酯、磺醯基酯、硫酯、醯胺或磺醯胺連接至胺基酸側鏈或連接至間隔子。
因此,應瞭解,生物素基取代基較佳包括順丁烯二醯亞胺基、醯基、磺醯基、N原子、O原子或S原子,其形成酯、磺醯基酯、硫酯、醯胺或磺醯胺之部分。
在較佳實施例中,生物素部分首先與間隔子偶合,之後間隔子與肽偶合。可購得多種具有使得能夠與離胺酸或半胱胺酸之側鏈偶合之間隔子官能基的生物素-間隔子結合物。在更佳實施例中,生物素-間隔子結合物含有可選擇性地與半胱胺酸側鏈上之硫氫基偶合之順丁烯二醯亞胺官能基。
根據本發明可用之生物素基取代基之實例包括:
a)
生物素被稱作維生素H或輔酶R且為水溶性B-複合維生素(維生素B7)。已表明其增加某些藥物之經口吸收。
或者或另外,本發明化合物中之一或多個胺基酸側鏈可結合至聚合部分例如以增加活體內(例如在血漿中)溶解度及/或半衰期及/或生物可用性。亦已知該修飾降低治療性蛋白質及肽之清除率(例如腎清除率)。
聚合部分較佳具水溶性(兩性或親水性)、無毒性且呈醫
藥學惰性。適合之聚合部分包括聚乙二醇(PEG)、PEG之均聚物或共聚物、PEG之單甲基取代聚合物(mPEG)或聚氧乙烯甘油(POG)。參見例如Int.J.Hematology 68:1(1998);Bioconjugate Chem.6:150(1995);及Crit.Rev.Therap.Drug Carrier Sys.9:249(1992)。
其他適合之聚合部分包括聚胺基酸,諸如聚離胺酸、聚天冬胺酸及聚麩胺酸(參見例如Gombotz等人,(1995),Bioconjugate Chem.,第6卷:332-351;Hudecz等人,(1992),Bioconjugate Chem.,第3卷,49-57;Tsukada等人,(1984),J.Natl.Cancer Inst.,第73卷:721-729;及Pratesi等人,(1985),Br.J.Cancer,第52卷:841-848)。
聚合部分可為直鏈或分支鏈。其可具有500-40,000 Da,例如500-10,000 Da、1000-5000 Da、10,000-20,000 Da或20,000-40,000 Da之分子量。
本發明化合物可包含兩個或兩個以上該等部分,在此情形下所有該等部分之總分子量通常將在上文提供之範圍內。
聚合部分可與胺基酸側鏈之胺基、羧基或硫醇基團偶合(藉由共價鍵聯)。較佳實例為Cys殘基之硫醇基團及Lys殘基之ε胺基,且亦可使用Asp及Glu殘基之羧基。
熟練操作者將充分知曉可用於進行偶合反應之適合技術。舉例而言,帶有甲氧基之PEG部分可使用購自Nektar Therapeutics AL之試劑,藉由順丁烯二醯亞胺基鍵聯與Cys硫醇基團偶合。亦參見WO 2008/101017及上文關於適
合化學詳情引用之參考案。
在本發明之一些實施例中,經順丁烯二醯亞胺官能化之PEG結合至半胱胺酸之側鏈硫氫基。
本發明之肽結合物具有腸促胰島素類似物-4之一或多種生物活性及胃泌素之一或多種生物活性。
在不存在胃泌素樣組分Y(Ya,Yb)及任何連接子組分L(La,Lb)下,肽Z(Za,Zb)具有腸促胰島素類似物-4之一或多種生物活性。亦即化合物R1-Z-R2將具有腸促胰島素類似物-4之該一或多種生物活性。
在不存在腸促胰島素類似物-4樣組分Z(Za,Zb)及任何連接子組分L(La,Lb)下,肽Y(Ya,Yb)具有胃泌素之一或多種生物活性。亦即化合物R1-Y-R2將具有胃泌素之該一或多種生物活性。
腸促胰島素類似物-4之生物活性可為對於GLP-1受體之促效劑活性。胃泌素之生物活性可為對於CCK-B受體之促效劑活性。
促效劑活性較佳係對於人類GLP-1受體及/或人類CCK-B受體。「促效劑活性」可包含對於結合至相關受體而誘發細胞內環狀AMP(cAMP)合成或pERK磷酸化之能力。
因此,相關化合物與GLP-1或CCK-B受體之結合可用作對促效劑活性之指示,但一般而言較佳使用量測由化合物與相關受體結合引起之細胞內信號傳導的生物分析。舉例而言,適合促效劑活化GLP-1受體將刺激細胞cAMP形成。
類似地,適合促效劑活化CCK-B受體將刺激細胞pERK磷酸化。因此,在表現該兩種受體之一者之適合細胞中cAMP之產生或ERK(pERK)之磷酸化可用於監測相關受體活性。使用一對適合細胞類型(各自表現一種受體而不表現另一種受體)因此可用於確定對於兩種受體類型之促效劑活性。
熟習此項技術者將知曉適合之分析形式,且下文提供實例。分析可採用人類GLP-1受體(NP_002053.3 GI:166795283)及/或人類CCK-B受體(NM_176875.3 GI:356995851)。當提及前驅體蛋白之序列時,當然應瞭解分析可利用缺少信號序列之成熟蛋白。
在一個較佳實施例中,本發明之多肽對於GLP1-R可具有低於0.1 nM之EC50值。
在一些實施例中,本發明之多肽對於CCKB-R可具有低於100 nM之EC50值。
在一個較佳實施例中,本發明之多肽對於CCKB-R可具有低於50 nM之EC50值。
應如實例4中所述量測EC50值。
本發明之肽結合物之用途亦涵蓋其醫藥學上可接受之鹽或溶劑合物之用途。
本發明之肽結合物可為代謝疾病或病症(包括糖尿病(尤其是1型及/或2型糖尿病)及肥胖)提供具吸引力之治療選擇。
糖尿病包含一組代謝疾病,其特徵為由胰島素分泌、胰島素作用或其兩者之缺陷所致的高血糖症。糖尿病之急性病征包括尿液產生過多、隨之發生代償性口渴及液體攝入增加、視力模糊、不明原因體重減輕、嗜睡及能量代謝變化。糖尿病之慢性高血糖症與大血管及微血管併發症有關,該等併發症可導致各種器官(尤其是眼睛(特別以糖尿病性視網膜病形式)、腎臟(以糖尿病性腎病變形式)、神經(以糖尿病性神經病形式)、心臟及血管)之長期損害、功能障礙且(在某些情況下)最終衰竭。糖尿病可基於病原特徵再分為三類,即1型糖尿病、2型糖尿病及妊娠期糖尿病。
1型糖尿病佔所有糖尿病病例之5-10%且由分泌胰島素之胰腺β-細胞之自體免疫破壞引起。
2型糖尿病佔糖尿病病例之90-95%且為代謝病症複雜集合之結果。2型糖尿病係內源性胰島素產生及/或全身胰島素敏感性不足以將血漿葡萄糖含量維持在診斷臨限值以下之結果。
妊娠期糖尿病係指在懷孕期間識別之任何程度之葡萄糖耐受不良。
亦意識到稱作糖尿病前期之病狀。其包括例如空腹葡萄糖含量升高及葡萄糖耐受性異常,且通常係指在血糖含量升高但低於關於臨床診斷糖尿病所確立之含量時發生之彼等狀況。
大部分2型糖尿病及糖尿病前期個體由於其他代謝風險因素之高普遍性而存在增加之發病率及死亡率風險,該等
代謝風險因素包括腹部肥胖(腹部內部器官周圍存在過多脂肪組織)、致動脈粥樣硬化性血脂異常(血脂病症,包括高三酸甘油酯含量、低HDL膽固醇含量及/或高LDL膽固醇含量,其促進動脈壁中之斑塊積聚)、血壓升高(高血壓)、血栓前狀態(例如血液中之高血纖維蛋白原或纖維蛋白溶酶原活化因子抑制劑-1含量)及促發炎狀態(例如血液中之C-反應性蛋白含量升高)。
相反,肥胖使得發展例如糖尿病前期、2型糖尿病、某些類型之癌症、阻塞性睡眠呼吸暫停及膽囊疾病之風險增加。
血脂異常與心血管疾病風險增加有關。由於血漿高密度脂蛋白(HDL)濃度與動脈粥樣硬化疾病風險之間存在逆相關性,因此HDL具有臨床重要性。動脈粥樣硬化斑塊中儲存之大部分膽固醇源自低密度脂蛋白(LDL),且因此LDL之濃度升高與動脈粥樣硬化密切相關。HDL/LDL比率係尤其用於評估動脈粥樣硬化及冠狀動脈粥樣硬化之臨床風險的參數。
不受任何特定理論限制,本發明之肽結合物似乎可出乎意料地以使得所觀測之活性可顯著大於在採用個別肽組分之相應附加(非結合)組合時所觀測之活性的方式組合GLP-1受體促效劑之生理學作用與胃泌素肽之生理學作用(參見上文)。因此,咸信本發明之肽結合物可尤其有益於治療糖尿病前期、糖尿病(尤其是1型及/或2型糖尿病)及糖尿病相關病狀、諸如上文論述之彼等疾病或病症,包括治療以
促進胰島β-細胞形成(胰島新生)且藉此促進胰島素產生,就血糖濃度之調節而言其將為有利的。本發明之肽結合物因此可尤其用於限制或阻止1型及/或2型糖尿病中之疾病進展。
本發明之肽可進一步適用於促進胰島中之β-細胞存活且抑制其細胞凋亡。GLP-1及胃泌素之作用包括對β-細胞增殖及成熟之作用,並且防止β-細胞凋亡及/或壞死且增強新生,因此本發明之肽之作用可包括該等作用及其對於改善胰島素及葡萄糖調節之作用。
本發明之肽結合物可因此適用作用於治療本文所述任何疾病、病症或病狀之醫藥劑。例示性疾病、病症或病狀包括胰島素抗性、葡萄糖耐受不良、糖尿病前期、與血糖含量升高相關之疾病病況(例如空腹血糖含量升高)、1型及/或2型糖尿病、高血糖症、胃病、代謝症候群、高血壓及/或血脂異常(或該等代謝風險因素之組合)、動脈粥樣硬化、動脈硬化、冠心病、微血管疾病、大血管疾病、周邊動脈疾病、中風、癌症(例如結腸癌)、發炎性腸病(IBD)、大腸急躁症(IBS)、糖尿病性神經病、糖尿病性視網膜病、糖尿病性腎病變及腎衰竭。
例示性治療作用包括預防體重增加、促進體重減輕、減少過重體重及/或治療肥胖(例如藉由控制食慾、進食、食物攝取、熱量攝取及/或能量消耗),包括病態肥胖以及相關疾病、病症及健康病狀,包括(但不限於)肥胖相關炎症、肥胖相關膽囊疾病及肥胖誘發之睡眠呼吸暫停。本發
明之肽結合物對該等病狀之作用可經由對體重之作用而整體或部分調節,或可不依賴於其。
下文中,應瞭解,提及在醫藥組合物中包含一或多種本發明之肽結合物亦涵蓋包含本發明之肽結合物之醫藥學上可接受之鹽或溶劑合物。
本發明之肽結合物可調配成適合經儲存或不經儲存而投藥且一般包含治療有效量之至少一種本發明之肽結合物以及醫藥學上可接受之載劑、賦形劑或媒劑的醫藥組合物。
術語「醫藥學上可接受之載劑」包括任何標準醫藥載劑。用於治療用途之醫藥學上可接受之載劑在醫藥技術中熟知且例如描述於「Remington's Pharmaceutical Sciences」,第17版,Alfonso R.Gennaro(編),Mark Publishing Company,Easton,PA,USA,1985中。舉例而言,可使用微酸性或生理學pH值下之無菌鹽水及磷酸鹽緩衝鹽水。適合之pH值緩衝劑可為例如磷酸鹽、檸檬酸鹽、乙酸鹽、參(羥甲基)胺基甲烷(TRIS)、N-參(羥甲基)甲基-3-胺基丙烷磺酸(TAPS)、碳酸氫銨、二乙醇胺、組胺酸、精胺酸、離胺酸或乙酸鹽(例如乙酸鈉)或其混合物。該術語另外涵蓋US Pharmacopeia中列舉用於動物(包括人類)之任何載劑。
本發明之醫藥組合物可為單位劑型。以此形式,該組合物可分為含有適當量活性組分之單位劑量。單位劑型可呈現為封裝製劑,該封裝含有離散量之製劑,例如封裝於小
瓶或安瓿中之錠劑、膠囊或散劑。單位劑型亦可為例如其自身之膠囊、扁囊劑或錠劑,或其可為適當數量之任何該等封裝形式。單位劑型亦可以單一劑量可注射形式提供,例如以含有液相(一般含水)組合物之筆裝置形式。組合物可經調配用於任何適合投藥途徑及方式。醫藥學上可接受之載劑或稀釋劑包括用於適合例如經口、玻璃體內、直腸、陰道、經鼻、局部、經腸或非經腸(包括皮下(SC)、肌肉內(IM)、靜脈內(IV)、皮內及經皮)投藥或吸入投藥之調配物中之彼等載劑或稀釋劑。調配物宜呈現為單位劑型且可由醫藥調配技術中熟知之任何方法來製備。
皮下或經皮投藥方式尤其可適用於本發明之肽結合物。
本發明之另一態樣係關於用於遞送本發明之醫藥調配物之裝置、劑型及封裝。因此,如此項技術中所熟知,呈本文所述之穩定或保藏調配物或溶液之至少一種肽結合物或特定部分或變異體可根據本發明經由多種遞送方法投與患者,該等遞送方法包括SC或IM注射;經皮、肺部、經黏膜、植入、滲透泵、筒、微量泵,或熟習此項技術者瞭解之其他方式。
本發明之又一態樣係關於經口調配物及投藥。用於經口投藥之調配物可依賴共投與佐劑(例如間苯二酚及非離子界面活性劑,諸如聚氧乙烯油基醚及正十六基聚乙烯醚)以人工增加腸壁之滲透性,以及共投與酶抑制劑(例如胰腺胰蛋白酶抑制劑、二異丙基氟磷酸酯(DFF)及抑肽酶)以抑制酶降解。用於經口投藥之固體劑型之活性成分化合物
可與至少一種添加劑混合,包括蔗糖、乳糖、纖維素、甘露糖醇、海藻糖、棉子糖、麥芽糖醇、聚葡萄糖、澱粉、瓊脂、精胺酸鹽(arginate)、甲殼素、聚葡萄胺糖、果膠、黃蓍膠、阿拉伯膠(gum arabic)、明膠、膠原蛋白、酪蛋白、白蛋白、合成或半合成聚合物及甘油酯。該等劑型亦可含有其他類型之添加劑,例如非活性稀釋劑、潤滑劑(諸如硬脂酸鎂、對羥基苯甲酸酯)、防腐劑(諸如山梨酸、抗壞血酸、α-生育酚)、抗氧化劑(諸如半胱胺酸)、崩解劑、黏合劑、增稠劑、緩衝劑、pH調節劑、甜味劑、調味劑、香味劑等。
本發明中所用之本發明肽結合物之典型劑量可在每天每公斤體重約0.0001至約100 mg之範圍內,諸如每天每公斤體重約0.0005至約50 mg,諸如每天每公斤體重約0.001至約10 mg,例如每天每公斤體重約0.01至約1 mg,以一或多劑,諸如一至三劑投與。如上文所示至某種程度,所用正確劑量將尤其取決於:欲治療疾病或病症之性質及嚴重度;欲治療個體之性別、年齡、體重及一般狀況;正接受或欲接受治療之其他可能併發疾病或病症;以及將為熟習此項技術之醫學實踐者所知之其他因素。
本發明之肽結合物可視熟練實踐者為特定個體選擇之所需劑量及醫藥組合物而定連續投與(例如藉由靜脈內投藥或另一連續藥物投與方法)或以一定間隔(一般為規則時間間隔)投與個體。規則投藥給藥間隔包括例如每天一次、
每天兩次、每兩天一次、每三天一次、每四天一次、每五天一次或每六天一次,每週一或兩次、每月一或兩次及其類似間隔。本發明之該等規則肽結合物投藥方案在某些情況下(諸如在慢性長期投藥期間)宜中斷一定時間間隔以便於經藥物治療之個體減少服藥量或停止服藥,通常稱作採用「藥物假期(drug holiday)」。藥物假期適用於例如維持或重獲藥物敏感性(尤其是在長期慢性治療期間)或減少藥物長期慢性治療對個體之不利副作用。藥物假期之定時取決於規則給藥方案之定時及採用藥物假期之目的(例如為了重獲藥物敏感性及/或減少連續長期投藥之不利副作用)。在一些實施例中,藥物假期可為藥物減少(例如低於治療有效量維持一定時間間隔)。在其他實施例中,在再次開始投藥之前,在相同或不同給藥方案(例如以較低或較高劑量及/或投藥頻率)下停止投與藥物歷時一定時間間隔。本發明之藥物假期因此可選自廣泛範圍之時間及劑量方案。例示性藥物假期為兩天或兩天以上、一週或一週以上、一個月或一個月以上、至多約24個月之藥物假期。因此,舉例而言,本發明肽結合物之規則每日給藥方案可中斷一週、兩週或四週之藥物假期,此後恢復每日或每週給藥時程。預想適用於投與本發明之肽結合物的多種其他藥物假期方案。
如上所述,應瞭解下文中提及本發明之肽結合物亦延伸至其醫藥學上可接受之鹽或溶劑合物以及包含一種以上不
同本發明肽結合物的組合物。
本發明之肽結合物可作為組合療法之部分連同另一活性劑一起投與用於治療所關注之疾病或病症,例如糖尿病、肥胖、代謝症候群、血脂異常或高血壓,且在該等情形下,兩種活性劑可一起或單獨給予,例如作為同一醫藥組合物或調配物中之組分或作為單獨調配物。
因此,本發明之肽結合物可與已知類型之抗糖尿病劑組合使用,包括(但不限於)二甲雙胍、磺醯脲、格列奈(glinide)、DPP-IV抑制劑、格列酮(glitazone)或胰島素或胰島素類似物。在一個較佳實施例中,本發明之肽結合物與胰島素或其類似物、DPP-IV抑制劑、磺醯脲或二甲雙胍組合,尤其與磺醯脲或二甲雙胍組合投與用於達成適當血糖控制。在一個更佳實施例中,肽結合物與胰島素或胰島素類似物組合投與用於達成適當血糖控制。適當胰島素類似物之實例包括(但不限於)LantusTM、NovorapidTM、HumalogTM、NovomixTM、ActraphaneTM HM、LevemirTM DegludecTM及ApidraTM。就此而言,其他相關抗糖尿病劑包括GLP-1受體促效劑,諸如艾塞那肽(exenatide)(ByettaTM;腸促胰島素類似物-4)及Byetta LARTM、利西拉來(lixisenatide)(LyxumiaTM)及利拉魯肽(liraglutide)(VictozaTM)。
本發明之肽結合物亦可與已知類型之抗肥胖劑組合使用,包括(但不限於)肽YY或其類似物、神經肽Y(NPY)或其類似物、大麻受體(cannabinoid receptor)1拮抗劑、脂
酶抑制劑、人類前胰島肽(HIP)、黑色素皮質素受體4促效劑、利拉魯肽、OrlistatTM及SibutramineTM或黑色素濃集激素受體1拮抗劑、CCK、澱粉素或瘦素及其類似物。
本發明之肽結合物可另外與已知類型之抗高血壓劑組合使用,包括(但不限於)血管收縮素-轉化酶抑制劑、血管收縮素II受體阻斷劑、利尿劑、β-阻斷劑或鈣通道阻斷劑。
本發明之肽結合物可另外與已知類型之抗血脂異常劑組合使用,包括(但不限於)史他汀(statin)、纖維酸酯(fibrate)、菸鹼酸及/或膽固醇吸收抑制劑。
本發明之肽結合物亦可與已知類型之質子泵抑制劑(亦即具有作為抑制劑H+/K+-ATP酶之藥理活性的醫藥劑)組合使用,包括(但不限於)苯并咪唑衍生物類型之藥劑或咪唑并吡啶衍生物類型之藥劑,諸如OmeprazoleTM、LansoprazoleTM、DexlansoprazoleTM、EsomeprazoleTM、PantoprazoleTM、RabeprazoleTM、ZolpidemTM、AlpidemTM、SaripidemTM或NecopidemTM。
此外,本發明之肽結合物可與已知類型之消炎劑組合使用,包括(但不限於):類固醇及皮質類固醇,諸如倍氯米松(beclomethasone)、甲潑尼龍(methylprednisolone)、倍他米松(betamethasone)、潑尼松(prednisone)、地塞米松(dexamethasone)及氫化可的松(hydrocortisone);非類固醇消炎劑(NSAID),諸如丙酸衍生物(例如阿明洛芬(alminoprofen)、苯噁洛芬(benoxaprofen)、布氯酸
(bucloxic acid)、卡洛芬(carprofen)、芬布芬(fenbufen)、芬洛芬(fenoprofen)、氟洛芬(fluprofen)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、吲哚洛芬(indoprofen)、酮洛芬(ketoprofen)、咪洛芬(miroprofen)、萘普生(naproxen)、噁丙嗪(oxaprozin)、吡洛芬(pirprofen)、普拉洛芬(pranoprofen)、舒洛芬(suprofen)、噻洛芬酸(tiaprofenic acid)及硫噁洛芬(tioxaprofen));乙酸衍生物(例如吲哚美辛(indomethacin)、阿西美辛(acemetacin)、阿氯芬酸(alclofenac)、環氯茚酸(clidanac)、雙氯芬酸(diclofenac)、芬氯酸(fenclofenac)、芬克洛酸(fenclozic acid)、芬替酸(fentiazac)、呋羅芬酸(furofenac)、異丁芬酸(ibufenac)、伊索克酸(isoxepac)、歐比那酸(oxpinac)、舒林酸(sulindac)、硫平酸(tiopinac)、托美汀(tolmetin)、齊多美辛(zidometacin)及佐美酸(zomepirac));芬那酸(fenamic acid)衍生物(例如氟芬那酸(flufenamic acid)、甲氯滅酸(meclofenamic acid)、甲芬那酸(mefenamic acid)、尼氟酸(niflumic acid)及托芬那酸(tolfenamic acid));聯苯基羧酸衍生物(例如二氟尼柳(diflunisal)及氟苯柳(flufenisal));昔康類(oxicams)(例如伊索昔康(isoxicam)、吡羅昔康(piroxicam)、舒多昔康(sudoxicam)及替諾昔康(tenoxicam));水楊酸酯類(例如乙醯基水楊酸及柳氮磺胺吡啶(sulfasalazine));及二氫吡唑酮類(例如阿紮丙宗(apazone)、貝比派瑞(bezpiperylon)、非普拉宗(feprazone)、莫非布宗(mofebutazone)、羥布宗
(oxyphenbutazone)及保泰松(phenylbutazone));COX II抑制劑,諸如羅非昔布(rofecoxib)及塞內昔布(celecoxib);干擾素β製劑(例如干擾素β-1a或干擾素β-1b);及某些其他化合物,諸如5-胺基水楊酸及其前藥及醫藥學上可接受之鹽。
亦已證明二甲雙胍具有消炎性質[參見Haffner等人,Diabetes 54:1566-1572(2005)]且因此亦可適用於本發明之情形。
以下實例論證本發明之某些特定實施例。除非另外詳細描述,否則使用如此項技術熟知且常規之標準技術進行以下實例。應瞭解,該等實例僅出於說明性目的且不應意謂對本發明之條件或範疇的完全限定。因此,其決不應被視為限制本發明之範疇。
實例中採用之縮寫包括:
NMP:N-甲基吡咯啶酮
DCM:二氯甲烷
DMF:N,N-二甲基甲醯胺
HATU:六氟磷酸2-(7-氮雜-1H-苯并三唑-1-基)-1,1,3,3-四甲基
DIPEA:二異丙基乙胺
EtOH:乙醇
Et2O:乙醚
8Ado:8-胺基-3,6-二氧雜辛醯基
8Aoc:8-胺基辛醯基
TFA:三氟乙酸
MeCN:乙腈
HPLC:高效液相層析
MS:質譜
IBMX:3-異丁基-1-甲基黃嘌呤
BSA:牛血清白蛋白
cAMP:環單磷酸腺苷
DMEM:達爾伯克改質之伊格爾培養基(Dulbecco's Modified Eagle Medium)
FCS:胎牛血清
HEPES:N-2-羥乙基哌嗪-N'-2-乙烷磺酸
p-ERK:磷酸化細胞外調節激酶
PBS:磷酸鹽緩衝鹽水
Boc:第三丁氧羰基
NEP:N-乙基吡咯啶酮
利拉魯肽:[Arg34,Lys26(十六醯基-異Glu)]GLP-1(7-37)
除非另外說明,否則下文採用之試劑及溶劑可以標準實驗室試劑或分析級別購得,且不經進一步純化即使用。
使用標準Fmoc化學在CEM Liberty肽合成器上進行固相肽合成。使用之前將TentaGelTM S Ram樹脂(1 g;0.25
mmol/g)於NEP(10 ml)中膨脹且使用DCM及NEP在小管與反應容器之間轉移。適當時使用假脯胺酸(其為用於使得肽合成期間之凝集最小化之二肽,諸如Fmoc-Phe-Thr(ψ-Me,Me-Pro)-OH及Fmoc-Asp-Ser(ψ-Me,Me-Pro)-OH),且採用非天然胺基酸(亦即Fmoc-8Ado-OH)而不對通用程序進行任何改變。
將NEP/DMF/DCM(1:1:1;0.2 M;5 ml)中之Fmoc-胺基酸連同HATU/DMF(0.5 M;2 ml)及DIPEA/NEP(2.0 M;1 ml)一起添加至CEM Discover微波裝置中之樹脂中。將偶合混合物加熱至75℃並持續5 min,同時使氮氣鼓泡穿過混合物。隨後以NEP(4×10 ml)洗滌樹脂。
向樹脂中添加哌啶/NEP(1/4(表示1份哌啶對4份NEP);10 ml)用於初始去保護,且微波加熱混合物(40℃;30秒)。抽乾反應容器且添加第二份哌啶/NEP(1/4;10 ml)且再次加熱(75℃;3 min)。隨後以NEP(6×10 ml)洗滌樹脂。
以EtOH(3×10 ml)及Et2O(3×10 ml)洗滌樹脂且在室溫(r.t.)下乾燥至恆重。藉由以TFA/TIS/H2O(90/5/5;40 ml;2 h;r.t.)處理使粗肽自樹脂裂解。在減壓下移除大部分TFA,且使粗肽沈澱並以Et2O洗滌三次,且在室溫下乾燥至恆重。
使用裝配有適合管柱及溶離份收集器且以緩衝液A(0.1% TFA,水溶液)與緩衝液B(0.1% TFA,90% MeCN,水溶液)之梯度運作之PerSeptive Biosystems VISION Workstation,藉由製備型逆相HPLC將粗肽純化至大於90%之純度。藉由分析型HPLC及MS分析溶離份且將相關溶離份收集並凍乾。藉由HPLC及MS表徵最終產物。
在CEM Liberty肽合成器上使用如上所述之TentaGel S Ram樹脂(1.13 g;0.24 mmol/g)及Fmoc化學合成[Leu14]腸促胰島素類似物-4(1-28)-8Ado-8Ado-[Leu4]胃泌素6。在連接點處採用Fmoc-8-胺基-3,6-二氧雜辛酸(Fmoc-8Ado-OH)以及Fmoc-Lys(Dde)-OH以便於醯化。
以NMP(3×2 min)洗滌樹脂結合之受保護線性肽。使用DCM(4 ml)中之Boc2O(265 mg)及DIPEA(47 μl)使固相連接肽之N端經Boc保護且以NMP(5×2 min)洗滌。隨後使用水合肼/NEP(4/96;2×15 min)裂解Dde保護基團,且以NMP(5×2 min)、DIEA/NMP(1/9;3×5 min)及NMP(8×2 min)洗滌樹脂。如上所述使用Fmoc-Glu-OtBu及十六酸,在CEM Liberty肽合成器上完成合成。
如上所述自樹脂裂解肽,且在Gemini-NX管柱(5×25 cm;10 μm;C18)上以緩衝液A(0.1% TFA;水溶液)與緩衝液B(0.1% TFA;90% MeCN;水溶液)混合物之35 ml/min流進行純化。以30%至65%緩衝液B之線性梯度經47
min溶離產物,且以溶離份收集器收集溶離份(9 ml)。藉由分析型HPLC及MS分析相關溶離份,收集且凍乾,產生白色粉末(39 mg),其經分析型HPLC分析為81%純。如由MS所測定,質量為4655.53 Da(計算值4655.44 Da)。
如上所述使用2份TentaGel S Ram樹脂(1.12 g;0.25 mmol/g)及Fmoc化學,使用Fmoc-Phe-Thr(ψ-Me,Me-Pro)-OH及Fmoc-8-胺基-3,6-二氧雜辛酸(Fmoc-8Ado-OH)在CEM Liberty肽合成器上合成[Cys16,Leu14]腸促胰島素類似物-4(1-28)-8Ado-8Ado-[Leu4]胃泌素6。如上所述自樹脂(1號部分)裂解肽。
l號純化:在Gemini-NX管柱(5×25 cm;10 μm;C18)上以緩衝液A(0.1% TFA;水溶液)與緩衝液B(0.1% TFA;90% MeCN;水溶液)混合物之35 ml/min流純化來自1號樹脂之粗肽。以30%至65%緩衝液B之線性梯度經47 min溶離產物,且以溶離份收集器收集溶離份(9 ml)。藉由分析型HPLC及MS分析相關溶離份,彙集且凍乾,產生白色粉末(90 mg),其經分析型HPLC分析為68%純。
2號純化:在Gemini-NX管柱(10 mm×25 cm;5 μm;C18)上以緩衝液A(0.1% TFA;水溶液)與緩衝液B(0.1% TFA;90% MeCN;水溶液)混合物之4 ml/min流純化來自1號純化之產物。以30%至60%緩衝液B之線性梯度經47 min溶離產物,且以溶離份收集器收集溶離份(2 ml)。藉由分
析型HPLC及MS分析相關溶離份,彙集且凍乾,產生白色粉末(25 mg),其經分析型HPLC分析為91%純。
3號純化:在Gemini管柱(5×25 cm;10 μm;C18)上以緩衝液A(0.1% TFA;水溶液)與緩衝液B(0.1% TFA;90% MeCN;水溶液)混合物之35 ml/min流純化來自2號樹脂之粗肽。以30%至65%緩衝液B之線性梯度經47 min溶離產物,且以溶離份收集器收集溶離份(9 ml)。藉由分析型HPLC及MS分析相關溶離份,彙集且凍乾,產生白色粉末(129 mg),其經分析型HPLC分析為74%純。
4號純化:在Gemini-NX管柱(10 mm×25 cm;5 μm;C18)上以緩衝液A(0.1% TFA;水溶液)與緩衝液B(0.1% TFA;90% MeCN;水溶液)混合物之4 ml/min流純化來自2號及3號純化之合併產物。以30%至55%緩衝液B之線性梯度經47 min溶離產物,且以溶離份收集器收集溶離份(2 ml)。藉由分析型HPLC及MS分析相關溶離份,彙集且凍乾,產生白色粉末(32 mg)(其經分析型HPLC分析為73%純)及另一白色粉末(100 mg)(其經分析型HPLC分析為62%純)。
5號純化:在Gemini-NX管柱(10 mm×25 cm;5 μm;C18)上以緩衝液A(0.1% TFA;水溶液)與緩衝液B(0.1% TFA;90% MeCN;水溶液)混合物之4 ml/min流純化來自4號純化之合併產物。以30%至55%緩衝液B之線性梯度經47 min溶離產物,且以溶離份收集器收集溶離份(2 ml)。藉由分析型HPLC及MS分析相關溶離份,彙集且凍乾,產生白
色粉末(30 mg),其經分析型HPLC分析為90%純。如由MS所測定,質量為4320.24 Da(計算值為4320.12 Da)。
結合:將來自5號純化之產物溶解於PBS緩衝液(6 ml;pH 7.4)中,產生混濁溶液(pH 6.2)。將生物素-順丁烯二醯亞胺(10.7 mg)溶解於DMSO(1.1 ml)中且添加至肽溶液中。藉由分析型HPLC監測反應且在3小時後使用Gemini-NX管柱(10 mm×25 cm;5 μm;C18)以緩衝液A(0.1% TFA;水溶液)與緩衝液B60 55%緩衝液B之混合物之4 ml/min流經47 min純化,且以溶離份收集器收集溶離份(2 ml)。藉由分析型HPLC及MS分析相關溶離份,彙集且凍乾,產生白色粉末(18 mg),其經分析型HPLC分析為84%純。如由MS所測定,質量為4771.35 Da(計算值為4771.31 Da)。
如上所述使用TentaGel S Ram樹脂(1.10 g;0.25 mmol/g)及Fmoc化學,使用Fmoc-Phe-Thr(ψ-Me,Me-Pro)-OH在CEM Liberty肽合成器上合成肽。在Gemini-NX管柱(5×25 cm;10 μm;C18)上以緩衝液A(0.1% TFA;水溶液)與緩衝液B(0.1% TFA;90% MeCN;水溶液)混合物之35 ml/min流純化粗肽。以20%至50%緩衝液B之線性梯度經47 min溶離產物,且以溶離份收集器收集溶離份(9 ml)。藉由分析型HPLC及MS分析相關溶離份,彙集且凍乾,產生白色粉末(137 mg),其經分析型HPLC分析為78%純。如由MS所測定,質量為4208.11 Da(計算值為4208.09 Da)。
藉由使用來自Perkin-Elmer之FlashPlateTM cAMP套組,在由GLP-1(7-36)、腸促胰島素類似物-4(1-39)或本發明之結合物刺激受體後量測cAMP之誘發來評估本發明之肽結合物之活體外作用。簡言之,將表現人類GLP-1 R(經由轉染GLP-1 R之cDNA且選擇穩定純系而產生之穩定細胞株)之HEK293細胞以每孔40,000個細胞接種於塗佈有0.01%聚L-離胺酸之96孔微量滴定盤中,且在100 μl生長介質[DMEM、10% FCS、青黴素(100 IU/ml)、鏈黴素(100 μg/ml)]中之培養基中生長1天。分析當日,移除生長介質且以200 μl Tyrode緩衝液[Tyrode鹽(9.6 g/l)、10 mM HEPES、pH 7.4]洗滌細胞一次。在37℃下,將細胞在含有濃度遞增之測試化合物、100 μM IBMX及0.1% BSA之100 μl Tyrode緩衝液中培育15 min。藉由添加25 μl 0.5 M HCl中止反應且在冰上培育60 min。關於其他方法詳情,參見WO 2008/152403。
藉由在穩定表現人類CCK-B R(高親和力胃泌素受體;經由轉染CCK-B R之cDNA且選擇穩定純系而產生之穩定細胞株)之HEK293細胞中量測p-ERK(使用AlphaScreenTM SureFire p-ERK分析)來評估本發明之肽結合物及對照胃泌
素17類似物[Leu15]胃泌素17的活體內作用。如下進行胃泌素受體功效分析(AlphaScreenTM SureFire p-ERK分析):在第1天,將CCK-B R表現細胞以每孔20,000個細胞接種於塗佈有聚D-離胺酸之96孔盤中的100 μl生長介質[DMEM、10% FCS、青黴素(100 IU/ml)、鏈黴素(100 μg/ml)]中。將細胞在培育箱(37℃,5% CO2)中培育2天。隨後將生長介質更換為每孔80 μl無血清介質[DMEM、青黴素(100 IU/ml)、鏈黴素(100 μg/ml)]且繼續在培育箱中將細胞培育過夜。在分析當日,在20 μl無血清介質中添加遞增濃度之化合物,且將細胞在室溫下培育5 min。藉由快速倒轉盤丟棄刺激介質,且每孔添加60 μl 1×溶解緩衝液(來自SureFire分析套組)。關於其他詳情,參見WO 2011/134471。
以上述分析(亦即,人類GLP-1 R活化功效、人類CCK-B R活化功效)測試本發明之肽結合物。
在人類GLP-1受體(hGLP-1 R)活化分析中使用腸促胰島素類似物-4(1-39)作為陽性對照,且在人類CCK-B受體(hCCK-B R)活性分析中使用h[Leu15]胃泌素17作為陽性對照。
結果(EC50值,以nM計)總結於下表1中。
上表1中總結之結果表明,本發明之肽結合物為所關注兩種受體之有效促效劑,且其展示極其類似之活性水準。
對C57Bl L/6J小鼠給予100 nmol/kg單一皮下劑量之每種待測試肽。在5及30分鐘後及在1、2、4、6、16及24小時後獲取血液樣本。在每個時間點獲取來自兩隻小鼠之樣
本。血液採樣後立即藉由頸椎脫位法對小鼠施行安樂死。在固相萃取(SPE)之後,藉由液相層析質譜法(LC-MS/MS)分析血漿樣本。
db/db小鼠模型先前已用於評估潛在治療候選物之β-細胞保留作用[Rolin,B.等人,Am.J.Physiol.Endocrinol.Metab.283:E745-E752(2002)]。若干研究已證明胰腺胰島素含量與β-細胞質量之間的相關性[Rolin,B.等人(在上述引文中);Suarez-Pinzon,W.L.等人,Diabetes 54:2596-2601(2005);Suarez-Pinzon W.L.等人,Diabetes 57:3281-3288(2008)]。
將db/db小鼠根據HbA1c含量分為各種治療組。每天一次以皮下(SC)注射處理小鼠總共21天。注射體積為5 ml/kg。研究期間,每日記錄體重(BW)且用於投與體重相關劑量之肽。
在第16天,對動物進行口服葡萄糖耐受性測試。在投與葡萄糖之前(t=0時,基線)及投與葡萄糖長達2小時後量測
血糖。
結束時,量測血糖含量,且分析血液樣本之HbA1c含量。
藉由固定葡萄糖氧化酶方法(Elite Autoanalyser,Bayer,Denmark)測定完全血糖濃度(mM)。使用Cobas c111分析器(Roche Diagnostics,Mannheim,Germany)分析血液樣本之HbA1c。
腸促胰島素類似物-胃泌素雙重促效劑化合物18與化合物23兩者在處理16天之後均使空腹血糖含量降低。化合物18使空腹血糖含量降低之程度大於化合物23。兩種化合物在處理3週後均使HbA1c之血漿含量降低,兩種化合物之間無顯著差異(非成對雙尾t測試)。
化合物18與化合物23兩者在第16天之口服葡萄糖挑戰(oral glucose challenge)後均使得葡萄糖濃度曲線下之面積(AUC)降低(表3),其中化合物18使得葡萄糖濃度降低之程度大於化合物23。
最後,化合物18與化合物23兩者在3週研究過程期間均使得體重增益降低(表3),其中化合物18使得體重增益降低之程度大於化合物23。
△-HbA1c:在對db/db小鼠處理21天後,SC投與媒劑、化合物18(100 nmol/kg)及化合物23(100 nmol/kg)對△-HbA1c(%)含量(研究開始時之HbA1c含量減去結束時之HbA1c含量)之影響。數據以SEM平均值給出(每組n=11)。
(-)表示△-HbA1c含量大於0.5%,(+)表示△-HbA1c含量在0.25%與0.5%之間,(++)表示△-HbA1c含量在0%與0.25%之間,(+++)表示△-HbA1c含量低於0%。
OGTT曲線下之面積(AUC):在對db/db小鼠處理16天之後,由葡萄糖負載後的曲線下面積(AUC)所量測的SC投與媒劑、化合物18(100 nmol/kg)及化合物23(100 nmol/kg)對葡萄糖耐受性之影響。數據以SEM平均值給出(每組n=11)。(-)表示OGTT AUC大於3000 mM*min,(+)表示OGTT AUC在2000與3000 mM*min之間,(++)表示OGTT AUC在1000與2000 M*min之間,(+++)表示OGTT AUC低於1000 mM*min。
△-BW:在對db/db小鼠處理21天後,SC投與媒劑、化合物18(100 nmol/kg)及化合物23(100 nmol/kg)對△-BW(g)含量(研究開始時之BW減去結束時之BW)之影響。數據以SEM平均值給出(每組n=9-11)。(-)表示△BW大於8 g,(+)
表示△BW在6與8 g之間,(++)表示△BW在4與6 g之間,(+++)表示△BW低於4 g。
空腹BG:在對db/db小鼠處理16天後,SC投與媒劑、化合物18(100 nmol/kg)及化合物23(100 nmol/kg)對空腹血糖(mM)含量之影響。數據以SEM平均值給出(每組n=11)。(-)表示空腹BG大於12 mM,(+)表示空腹BG在8與12 mM之間,(++)表示空腹BG在6與8 mM之間,(+++)表示空腹BG低於6 mM。
將db/db小鼠根據HbA1c含量分為各種治療組。每天一次以皮下(SC)注射處理小鼠總計4週,此後對其以媒劑給藥歷時2週。注射體積為5 ml/kg。研究期間,每日記錄體重(BW)且用於投與體重相關劑量之肽。
在3週及5週後,對動物進行口服葡萄糖耐受性測試。在投與葡萄糖之前(t=0時,基線)及投與葡萄糖長達2小時後量測血糖。
藉由固定葡萄糖氧化酶方法(Elite Autoanalyser,Bayer,Denmark)測定完全血糖濃度(mM)。
腸促胰島素類似物-胃泌素雙重促效劑化合物18與媒劑
相比在處理3週後使空腹血糖含量降低。化合物18使空腹血糖含量降低之程度大於等莫耳劑量之利拉魯肽,參見圖1。4週處理後接著1週藥物假期(媒劑給藥)之後,化合物18與媒劑相比使空腹血糖含量顯著降低。化合物18使空腹血糖含量降低之程度大於等莫耳劑量之利拉魯肽,參見圖2。
化合物18在處理3週後在口服葡萄糖挑戰後使得葡萄糖濃度曲線下之面積(AUC)降低,其中化合物18使得葡萄糖濃度曲線(AUC)降低之程度大於利拉魯肽,參見圖3。
4週處理後接著1週藥物假期(媒劑給藥)之後,在口服葡萄糖挑戰後,化合物18與媒劑相比使葡萄糖濃度曲線下之面積(AUC)顯著降低,參見圖4。化合物18使葡萄糖濃度曲線(AUC)降低之程度大於等莫耳劑量之利拉魯肽。
最後,化合物18在4週研究過程期間使得體重增益減少,其中化合物18使得體重降低之程度大於等莫耳劑量之利拉魯肽,參見圖5。
將ZDF大鼠根據HbA1c含量分為各種治療組。每天兩次以皮下(SC)注射處理大鼠總計6週。注射體積為5 ml/kg。研究期間,每日記錄體重(BW)且用於投與體重相關劑量之肽。
5週後,對動物進行口服葡萄糖耐受性測試。在投與葡
萄糖之前(t=0時,基線)及投與葡萄糖長達2小時後量測血糖。
結束時,分析血液樣本之HbA1c含量。
藉由固定葡萄糖氧化酶方法(Elite Autoanalyser,Bayer,Denmark)測定完全血糖濃度(mM)。
使用Cobas c111分析器(Roche Diagnostics,Mannheim,Germany)分析血液樣本之HbA1c。
腸促胰島素類似物-胃泌素雙重促效劑化合物18與媒劑相比在處理5週後使空腹血糖含量降低。化合物18使空腹血糖含量降低之程度大於等莫耳劑量之利拉魯肽,參見圖6。
5週處理後,在口服葡萄糖挑戰後,化合物18使葡萄糖濃度曲線下之面積(AUC)降低,其中化合物18使葡萄糖濃度曲線(AUC)降低之程度大於利拉魯肽,參見圖7。
6週處理後,化合物18與媒劑相比使得HbA1c含量顯著降低。化合物18使得HbA1c含量降低之程度大於等莫耳劑量之利拉魯肽,參見圖8。
圖1處理3週後之空腹血糖含量對db/db小鼠處理3週後,每天一次皮下(SC)投與媒劑、利拉魯肽(每天100 nmol/kg)及化合物18(每天30及100
nmol/kg)對空腹血糖含量之影響。數據以SEM平均值給出。
統計學:藉由單因素ANOVA,繼而由Bonferroni's MC測試,相對於媒劑或相對於利拉魯肽來比較數據:***p<0.001相對於媒劑,##p<0.01相對於利拉魯肽。
圖2處理4週,繼而1週藥物假期後之空腹血糖含量對db/db小鼠處理4週、繼而1週藥物假期(媒劑處理)後,每天一次皮下投與媒劑、利拉魯肽(每天100 nmol/kg)及化合物18(每天30及100 nmol/kg)對空腹血糖含量之影響。數據以SEM平均值給出。
統計學:藉由單因素ANOVA,繼而由Bonferroni's MC測試,相對於媒劑或相對於利拉魯肽來比較數據:**p<0.01相對於媒劑,#p<0.05相對於利拉魯肽。
圖3處理3週後之OGTT,AUC對db/db小鼠處理3週後,每天一次皮下投與媒劑、利拉魯肽(每天100 nmol/kg)及化合物18(每天30及100 nmol/kg)對葡萄糖耐受性之影響。數據表述為SEM曲線下面積(AUC)。
統計學:藉由單因素ANOVA,繼而由Bonferroni's MC測試,相對於媒劑或相對於利拉魯肽來比較數據:***p<0.001相對於媒劑,###p<0.001相對於利拉魯肽。
圖4處理4週+1週藥物假期後之OGTT,AUC對db/db小鼠處理4週、繼而1週藥物假期(媒劑處理)後,每天一次皮下投與媒劑、利拉魯肽(每天100 nmol/kg)及化合
物18(每天30及100 nmol/kg)對葡萄糖耐受性之影響。數據表述為SEM曲線下面積(AUC)。
統計學:藉由單因素ANOVA,繼而由Bonferroni's MC測試,相對於媒劑或相對於利拉魯肽來比較數據:*p<0.05、***p<0.001相對於媒劑,###p<0.001相對於利拉魯肽。
圖5處理4週後之△體重對db/db小鼠處理4週後,每天一次皮下投與媒劑、利拉魯肽(每天100 nmol/kg)及化合物18(每天30及100 nmol/kg)對△(結束-開始)體重之影響。數據以SEM平均值給出。
統計學:藉由單因素ANOVA,繼而由Bonferroni's MC測試,相對於媒劑或相對於利拉魯肽來比較數據:***p<0.001相對於媒劑,##p<0.01相對於利拉魯肽。
圖6處理5週後之空腹血糖含量對ZDF大鼠處理5週後,每天兩次皮下投與媒劑、利拉魯肽(每天2×40 nmol/kg)及化合物18(每天2×10及2×40 nmol/kg)對空腹血糖含量之影響。數據以SEM平均值給出。
統計學:藉由單因素ANOVA,繼而由Bonferroni's MC測試,相對於媒劑或相對於利拉魯肽來比較數據:**p<0.01、***p<0.001相對於媒劑,###p<0.001相對於利拉魯肽。
圖7處理5週後之OGTT,AUC對db/db小鼠處理5週後,每天一次皮下投與媒劑、利拉魯
肽(每天2×40 nmol/kg)及化合物18(每天2×10及2×40 nmol/kg)對葡萄糖耐受性之影響。數據表述為SEM曲線下面積(AUC)。
統計學:藉由單因素ANOVA,繼而由Bonferroni's MC測試,相對於媒劑或相對於利拉魯肽來比較數據:***p<0.001相對於媒劑,###p<0.001相對於利拉魯肽。
圖8處理6週後之HbA1c含量對ZDF大鼠處理6週後,每天兩次皮下投與媒劑、利拉魯肽(每天2×40 nmol/kg)及化合物18(每天2×10及2×40 nmol/kg)對HbA1c含量之影響。數據以SEM平均值給出。
統計學:藉由單因素ANOVA,繼而由Bonferroni's MC測試,相對於媒劑或相對於利拉魯肽來比較數據:***p<0.001相對於媒劑,#p<0.05相對於利拉魯肽。
Claims (48)
- 一種具有式I之肽結合物:R1-Za-La-Ya-R2 (I)其中R1為H、C1-4烷基、乙醯基、甲醯基、苄醯基或三氟乙醯基;及R2為OH或NH2;Za為具有式Ia之肽序列His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Z9-Leu-Ser-Z12-Z13-Z14-Glu-Z16-Glu-Ala-Val-Z20-Leu-Phe-Ile-Z24-Z25-Leu-Z27-Z28 (Ia)其中Z9係選自Asp及Glu;Z12係選自Lys、Arg及Orn;Z13係選自Gln及Tyr;Z14係選自Met及Leu;Z16係選自Glu、Arg、Orn、Cys及Lys;Z20係選自Arg、Lys及Orn;Z24係選自Arg、Orn、Lys及Glu;Z25係選自Trp、Lys、Cys及Phe;Z27係選自Lys、Arg及Orn;及Z28係選自Asn及Asp或不存在;La為具有式Ib之肽序列L1-L2-L3-L4 (Ib) 其中L1係選自Orn、8Ado、Cys、Lys及Gln或不存在;L2係選自Orn、8Ado、Cys、Lys及Gln或不存在;L3係選自Orn、8Ado、Cys、Lys及Gln或不存在;及L4係選自Orn、8Ado、Cys、Lys及Gln或不存在;Ya為具有式Ic之肽序列Y12-Y13-Y14-Y15-Asp-Y17 (Ic);其中Y12係選自Tyr及Ala或不存在;Y13係選自Gly及Ala或不存在;Y14係選自Trp、1Nal及Phe;Y15係選自Met、Leu、Nle、Thr及Phe;及Y17係選自Phe及3-(3-吡啶基)-丙胺酸;其中在式Ia及Ib中Lys、Orn或Cys中之至少一者進一步結合至親脂性及/或生物素基取代基及/或經聚乙二醇化;或其醫藥學上可接受之鹽或溶劑合物。
- 如請求項1之肽結合物,其中Za為具有式IIa之肽序列His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Z9-Leu-Ser-Lys-Z13-Z14-Glu-Z16-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Z25-Leu-Lys-Z28 (IIa)其中Z9係選自Glu及Asp; Z13係選自Gln及Tyr;Z14係選自Met及Leu;Z16係選自Glu、Cys及Lys;Z25係選自Lys、Phe、Cys及Trp;及Z28係選自Asn及Asp或不存在;La為具有式Ib之肽序列;Ya為具有式IIc之肽序列Tyr-Gly-Trp-Y15-Asp-Phe (IIc)其中Y15係選自Leu及Thr;及其中在式IIa或式IIb之位置Z16或Z25中Lys或Cys中之至少一者進一步結合至親脂性及/或生物素基取代基及/或經聚乙二醇化;或其醫藥學上可接受之鹽或溶劑合物。
- 如請求項1或請求項2之肽結合物或其醫藥學上可接受之鹽或溶劑合物,其中該式I之肽序列係選自H-HGEGTFTSDLSKQLEEEAVRLFIEWLKN-8Ado-K(十六醯基-異Glu)-8Ado-YGWLDF-NH2 H-HGEGTFTSDLSKQLEEEAVRLFIE-K(十六醯基-異Glu)-LKN-8Ado-8Ado-YGWLDF-NH2 H-HGEGTFTSDLSKQLE-K(十六醯基-異Glu)-EAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2 H-HGEGTFTSDLSKQMEEEAVRLFIEWLKN-8Ado-C(生物素-Mal)-8Ado-YGWLDF-NH2 H-HGEGTFTSDLSKQLEEEAVRLFIE-C(生物素-Mal)-LKN-8Ado-8Ado-YGWLDF-NH2 H-HGEGTFTSDLSKQLE-C(生物素-Mal)-EAVRLFIEWL KN-8Ado-8Ado-YGWLDF-NH2 H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-LK-8Ado-8Ado-YGWLDF-NH2及H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-LK-8Ado-QQYGWLDF-NH2。
- 一種具有式III之肽結合物R1-Zb-Lb-Yb-R2 (III)其中R1為H、C1-4烷基、乙醯基、甲醯基、苄醯基或三氟乙醯基;R2為OH或NH2;Zb為具有式IIIa之肽序列His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Lys-Tyr-Leu-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Z25-Leu-Lys-Z28 (IIIa)其中Z25係選自Phe及Trp;及Z28係選自Asn及Asp或不存在;Lb為具有式IIIb之肽序列L5-L6-L7-L8 (IIIb)其中 L5係選自8Ado、8Aoc、Ala、Gly及Gln或不存在;L6係選自8Ado、8Aoc、Ala、Gly及Gln或不存在;L7係選自8Ado、8Aoc、Ala、Gly及Gln或不存在;及L8係選自8Ado、8Aoc、Ala、Gly及Gln或不存在;Yb為具有式IIIc之肽序列Y10-Y11-Tyr-Gly-Trp-Y15-Asp-Phe (IIIc)其中Y10為Glu或不存在;Y11為Ala或不存在;及Y15係選自Leu及Thr;或其醫藥學上可接受之鹽或溶劑合物;限制條件為式III不為H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Ado-8Ado-YGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLKYGWLDF-NH2;及H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Ado-YGWLDF-NH2。
- 如請求項4之肽結合物,其中Zb為具有式IVa之肽序列His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Lys-Tyr-Leu-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Z25-Leu-Lys-Asn (IVa)其中 Z25係選自Phe及Trp;及Lb為具有式IIIb之肽序列;Yb為具有式IVc之肽序列Tyr-Gly-Trp-Y15-Asp-Phe (IVc)其中Y15係選自Leu及Thr;或其醫藥學上可接受之鹽或溶劑合物。
- 如請求項4或請求項5之肽結合物或其醫藥學上可接受之鹽或溶劑合物,其中該式III之肽序列係選自H-HGEGTFTSELSKYLEEEAVRLFIEFLKQQYGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLKQQEAYGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Ado-QQYGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLKAAAYGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLKGGGYGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLK-8Aoc-YGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWLDF- NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLKAYGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-8Ado-8Ado-YGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLKD-8Ado-8Ado-YGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLKNYGWTDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLKDYGWTDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEWLKNYGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEWLKDYGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLKEAYGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-K(十六醯基-異Glu)-YGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-K(十六醯基-異Glu)-WLDF-NH2;H-HGEGTFTSELSKYLE-K(十六醯基-異Glu)-EAVRLFIEFLKNYGWLDF-NH2;H-HGEGTFTSELSKYLE-K(十六醯基-異Glu)-EAVRLFI EFLKNWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLK-K(十六醯基-異Glu)-YGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEFLK-K(十六醯基-異Glu)-WLDF-NH2;H-HGEGTFTSELSKYLE-K(十六醯基-異Glu)-EAVRLFIEFLKYGWLDF-NH2;H-HGEGTFTSELSKYLE-K(十六醯基-異Glu)-EAVRLFIEFLKWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-LK-8Ado-YGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-LKQQYGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-LK-Orn-Orn-YGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-LKNYGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIE-K(十六醯基-異Glu)-LKDYGWLDF-NH2;H-HGEGTFTSDLSKQLEEEAVRLFIEC(PEG5K)LKN-8Ado-8Ado-YGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEC(PEG10K)LK-8Ado-8Ado-YGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEC(PEG20K)LK- 8Ado-8Ado-YGWLDF-NH2;H-HGEGTFTSELSKYLEEEAVRLFIEC(PEG40K)LK-8Ado-8Ado-YGWLDF-NH2;H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNYGWTDF-OH;及H-HGEGTFTSELSKYLEEEAVRLFIEFLKN-8Ado-8Ado-YGWTDF-NH2。
- 如請求項1至6中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物,其中Za或Zb與原生吉拉毒蜥(Heloderma suspectum)腸促胰島素類似物-4(exendin-4)具有至少75%、80%、85%、90%或95%一致性。
- 如請求項1至6中任一項之肽結合物,其中Ya或Yb與原生人類胃泌素17及/或胃泌素6具有至少70%、80%、83%、85%、90%、94%或95%一致性。
- 如請求項1至8中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物,其係用作藥劑。
- 如請求項9之肽結合物或其醫藥學上可接受之鹽或溶劑合物,其係用作用於治療選自以下之疾病或病症的藥劑:1型糖尿病、2型糖尿病、糖尿病前期、胰島素抗性症候群、葡萄糖耐受性減低(IGT)、與血糖量升高相關之疾病病況、高血糖症、高血壓、致動脈粥樣硬化性血脂異常、動脈硬化(例如動脈粥樣硬化)、冠心病、周邊動脈疾病、中風、微血管疾病、胃病、代謝症候群、癌症(例 如結腸癌)、發炎性腸病(IBD)、大腸急躁症(IBS)、糖尿病性神經病、糖尿病性視網膜病、糖尿病性腎病變及腎衰竭。
- 如請求項9之肽結合物或其醫藥學上可接受之鹽或溶劑合物,其係用作誘發有需要之個體內胰腺β細胞及/或小島新生之藥劑。
- 如請求項9之肽結合物或其醫藥學上可接受之鹽或溶劑合物,其係用作誘發有需要之個體內胰島β-細胞存活之藥劑。
- 如請求項9之肽結合物或其醫藥學上可接受之鹽或溶劑合物,其係用作預防有需要之個體內胰島中β-細胞凋亡及/或壞死的藥劑。
- 如請求項9之肽結合物或其醫藥學上可接受之鹽或溶劑合物,其係用作誘發有需要之個體內胰島中β-細胞增殖的藥劑。
- 如請求項9之肽結合物或其醫藥學上可接受之鹽或溶劑合物,其係用作用於有需要之個體內胰島中誘發β-細胞新生、小島新生、β-細胞存活、β-細胞增殖及/或預防β-細胞凋亡及/或壞死之任何組合的藥劑。
- 如請求項9至15中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物,其中該個體為人類。
- 一種用於治療有需要之個體選自由以下組成之群之疾病或病症的方法:1型糖尿病、2型糖尿病、糖尿病前期、胰島素抗性症 候群、葡萄糖耐受性減低(IGT)、與血糖量升高相關之疾病病況、高血糖症、高血壓、致動脈粥樣硬化性血脂異常、動脈硬化(例如動脈粥樣硬化)、大血管疾病、冠心病、周邊動脈疾病、中風、微血管疾病、胃病、代謝症候群、癌症(例如結腸癌)、發炎性腸病(IBD)、大腸急躁症(IBS)、糖尿病性神經病、糖尿病性視網膜病、糖尿病性腎病變及腎衰竭,該方法包含向該有需要之個體投與治療有效量之如請求項1至16中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物。
- 一種用於預防有需要之個體選自由以下組成之群之疾病或病症的方法:1型糖尿病、2型糖尿病、糖尿病前期、胰島素抗性症候群、葡萄糖耐受性減低(IGT)、與血糖量升高相關之疾病病況、高血糖症、高血壓、致動脈粥樣硬化性血脂異常、動脈硬化(例如動脈粥樣硬化)、大血管疾病、冠心病、周邊動脈疾病、中風、微血管疾病、胃病、代謝症候群、癌症(例如結腸癌)、發炎性腸病(IBD)、大腸急躁症(IBS)、糖尿病性神經病、糖尿病性視網膜病、糖尿病性腎病變及腎衰竭,該方法包含向該有需要之個體投與治療有效量之如請求項1至16中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物。
- 如請求項18之方法,其中該個體為人類。
- 一種醫藥組合物,其包含如請求項1至16中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物及醫藥學上可接受之載劑、賦形劑或媒劑。
- 如請求項20之醫藥組合物,其係用於治療1型糖尿病、2型糖尿病、糖尿病前期、胰島素抗性症候群、葡萄糖耐受性減低(IGT)、與血糖量升高相關之疾病病況、高血糖症、高血壓、致動脈粥樣硬化性血脂異常、動脈硬化(例如動脈粥樣硬化)、大血管疾病、冠心病、周邊動脈疾病、中風、微血管疾病、胃病、代謝症候群、癌症(例如結腸癌)、發炎性腸病(IBD)、大腸急躁症(IBS)、糖尿病性神經病、糖尿病性視網膜病、糖尿病性腎病變及腎衰竭。
- 如請求項20之醫藥組合物,其係用於預防1型糖尿病、2型糖尿病、糖尿病前期、胰島素抗性症候群、葡萄糖耐受性減低(IGT)、與血糖量升高相關之疾病病況、高血糖症、高血壓、致動脈粥樣硬化性血脂異常、動脈硬化(例如動脈粥樣硬化)、大血管疾病、冠心病、周邊動脈疾病、中風、微血管疾病、胃病、代謝症候群、癌症(例如結腸癌)、發炎性腸病(IBD)、大腸急躁症(IBS)、糖尿病性神經病、糖尿病性視網膜病、糖尿病性腎病變及腎衰竭。
- 如請求項20之醫藥組合物,其係用於預防體重增加或促進體重減輕。
- 如請求項1至16中任一項之肽結合物或其醫藥學上可接 受之鹽或溶劑合物,其係用於選自改善循環葡萄糖含量、改善葡萄糖耐受性及/或改善循環膽固醇含量、降低循環LDL含量、提高HDL/LDL比率及其組合之方法。
- 如請求項1至16中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物,其係用於治療或預防過重體重所引起或為特徵之病狀的方法。
- 一種如請求項1至16中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物用於有需要之個體預防體重增加或促進體重減輕的用途。
- 一種如請求項1至16中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物在有需要之個體中改善循環葡萄糖含量、葡萄糖耐受性及/或循環膽固醇含量、降低循環LDL含量及/或提高HDL/LDL比率之方法中的用途。
- 如請求項1至27中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物、用途或方法,其中投與該化合物作為與質子泵抑制劑或用於治療或預防糖尿病、肥胖、血脂異常或高血壓之藥劑之組合療法的一部分。
- 如請求項28之肽結合物或其醫藥學上可接受之鹽或溶劑合物、用途或方法,其中該用於治療或預防糖尿病之藥劑為二甲雙胍(metformin)、磺醯脲、格列奈(glinide)、DPP-IV抑制劑、格列酮(glitazone)、胰島素或胰島素類似物。
- 如請求項28之肽結合物或其醫藥學上可接受之鹽或溶劑合物、用途或方法,其中該用於治療或預防肥胖之藥劑 為升糖素樣肽受體1促效劑、肽YY或其類似物、大麻受體(cannabinoid receptor)1拮抗劑、脂酶抑制劑、黑色素皮質素受體4促效劑或黑色素濃集激素受體1拮抗劑。
- 如請求項28之肽結合物或其醫藥學上可接受之鹽或溶劑合物、用途或方法,其中該用於治療或預防高血壓之藥劑為血管收縮素-轉化酶抑制劑、血管收縮素II受體阻斷劑、利尿劑、β-阻斷劑或鈣通道阻斷劑。
- 如請求項28之肽結合物或其醫藥學上可接受之鹽或溶劑合物、用途或方法,其中該用於治療或預防血脂異常之藥劑為史他汀(statin)、纖維酸酯(fibrate)、菸鹼酸及/或膽固醇吸收抑制劑。
- 如請求項28之肽結合物或其醫藥學上可接受之鹽或溶劑合物、用途或方法,其中該已知類型之質子泵抑制劑(亦即具有作為抑制劑H+/K+-ATP酶之藥理活性的藥劑)包括(但不限於)苯并咪唑衍生物類型之藥劑或咪唑并吡啶衍生物類型之藥劑。
- 一種合成製造如請求項1至16中任一項之肽結合物的方法。
- 一種重組製造如請求項1至16中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物結合物的方法。
- 一種如請求項1至16中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物的用途,其係用於有需要之個體選自改善循環葡萄糖含量、改善葡萄糖耐受性及/或改善循環膽固醇含量、降低循環LDL含量、提高HDL/LDL比 率及其組合之方法中,其中使用藥物假期給藥方案。
- 一種製造如前述請求項中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物的方法。
- 一種醫藥組合物,其包含如請求項1至16中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物,合併一或多種如請求項1至16之肽結合物或其醫藥學上可接受之鹽或溶劑合物連同醫藥學上可接受之載劑、賦形劑或媒劑。
- 一種裝置,其包含至少一種如請求項1至16中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物,其係用於遞送該肽結合物或其醫藥學上可接受之鹽或溶劑合物於個體。
- 一種套組,其包含至少一種如請求項1至16中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物及封裝或使用說明。
- 一種如請求項1至16中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物的用途,其係用於製備藥劑。
- 一種如請求項9之肽結合物或其醫藥學上可接受之鹽或溶劑合物的用途,其中該藥劑係用於治療或預防有需要之個體選自以下之疾病或病症:1型糖尿病、2型糖尿病、糖尿病前期、胰島素抗性症候群、葡萄糖耐受性減低(IGT)、與血糖量升高相關之疾病病況、高血糖症、高血壓、致動脈粥樣硬化性血脂異常、動脈硬化(例如動脈粥樣硬化)、大血管疾病、冠心 病、周邊動脈疾病、中風、微血管疾病、胃病、代謝症候群、癌症(例如結腸癌)、發炎性腸病(IBD)、大腸急躁症(IBS)、糖尿病性神經病、糖尿病性視網膜病、糖尿病性腎病變及腎衰竭。
- 如請求項41之肽結合物或其醫藥學上可接受之鹽或溶劑合物之用途,其中該藥劑係用於誘發有需要之個體內胰腺β細胞及/或小島新生。
- 如請求項41之肽結合物或其醫藥學上可接受之鹽或溶劑合物之用途,其中該藥劑係用於改善有需要之個體內胰島β-細胞之存活率。
- 如請求項41之肽結合物或其醫藥學上可接受之鹽或溶劑合物之用途,其中該藥劑係用於預防有需要之個體內胰島中β-細胞凋亡及/或壞死。
- 如請求項41之肽結合物或其醫藥學上可接受之鹽或溶劑合物之用途,其中該藥劑係用於誘發有需要之個體內胰島β-細胞之增殖。
- 如請求項41至46中任一項之肽結合物或其醫藥學上可接受之鹽或溶劑合物之用途,其中該個體為人類。
- 如請求項25之肽結合物或其醫藥學上可接受之鹽或溶劑合物,其中該過重體重所引起或為特徵之病狀係選自肥胖、病態肥胖、肥胖相關發炎、肥胖相關膽囊疾病、肥胖誘發之睡眠呼吸暫停、代謝症候群、糖尿病前期,該方法包含向該個體投與治療有效量之如請求項23之肽結合物或其醫藥學上可接受之鹽或溶劑合物。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161555435P | 2011-11-03 | 2011-11-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW201326194A true TW201326194A (zh) | 2013-07-01 |
Family
ID=47146385
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW101140873A TW201326194A (zh) | 2011-11-03 | 2012-11-02 | Glp-1胃泌素受體促效劑肽結合物 |
Country Status (13)
Country | Link |
---|---|
US (2) | US9259477B2 (zh) |
EP (1) | EP2773377B1 (zh) |
JP (1) | JP6359972B2 (zh) |
KR (1) | KR20140100947A (zh) |
CN (1) | CN104144704B (zh) |
AR (1) | AR088636A1 (zh) |
AU (1) | AU2012331053A1 (zh) |
BR (1) | BR112014010780A2 (zh) |
CA (1) | CA2853884A1 (zh) |
EA (1) | EA028951B9 (zh) |
MX (1) | MX2014005351A (zh) |
TW (1) | TW201326194A (zh) |
WO (1) | WO2013064669A1 (zh) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5969461B2 (ja) | 2010-04-27 | 2016-08-17 | ジーランド ファーマ アクティーゼルスカブ | Glp−1受容体作動薬とガストリンとのペプチド複合体及びその使用 |
WO2013064669A1 (en) | 2011-11-03 | 2013-05-10 | Zealand Pharma A/S | Glp-1 receptor agonist peptide gastrin conjugates |
US10093713B2 (en) | 2013-11-06 | 2018-10-09 | Zealand Pharma A/S | GIP-GLP-1 dual agonist compounds and methods |
TR201902516T4 (tr) | 2013-11-06 | 2019-03-21 | Zealand Pharma As | Glukagon-glp-1-gıp üçlü agonist bileşikleri. |
CN107001439B (zh) | 2014-10-29 | 2021-12-21 | 西兰制药公司 | Gip激动剂化合物及方法 |
WO2016168388A2 (en) | 2015-04-14 | 2016-10-20 | Palatin Technologies, Inc. | Therapies for obesity, diabetes and related indications |
WO2017152861A1 (en) * | 2016-03-10 | 2017-09-14 | Shenzhen Hightide Biopharmaceutical, Ltd. | Conjugates of islet neogenesis peptides and analogs, and methods thereof |
KR102502040B1 (ko) | 2016-12-09 | 2023-02-24 | 질랜드 파마 에이/에스 | 아실화 glp-1/glp-2 이중 효능제 |
KR102398777B1 (ko) * | 2017-06-29 | 2022-05-17 | 유레카 에스에이알엘 | 개선된 약학 특성을 갖는 프로드럭 펩티드 |
CN109248323B (zh) * | 2017-07-14 | 2023-09-08 | 杭州先为达生物科技有限公司 | 酰化的glp-1衍生物 |
CN109331173B (zh) * | 2018-12-17 | 2021-05-07 | 中国医学科学院医学实验动物研究所 | 胃泌素-二氧化硅微球及其用途 |
CN112759640B (zh) * | 2020-12-09 | 2023-09-08 | 江苏师范大学 | 一类glp-1/胃泌素受体双重激动剂及其应用 |
Family Cites Families (102)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4288627A (en) | 1980-02-12 | 1981-09-08 | Phillips Petroleum Company | Oxidation of thiols employing cobalt molybdate/triethylamine catalyst |
US5614492A (en) | 1986-05-05 | 1997-03-25 | The General Hospital Corporation | Insulinotropic hormone GLP-1 (7-36) and uses thereof |
US5118666A (en) | 1986-05-05 | 1992-06-02 | The General Hospital Corporation | Insulinotropic hormone |
US5120712A (en) | 1986-05-05 | 1992-06-09 | The General Hospital Corporation | Insulinotropic hormone |
US5545618A (en) | 1990-01-24 | 1996-08-13 | Buckley; Douglas I. | GLP-1 analogs useful for diabetes treatment |
DK0512042T3 (da) | 1990-01-24 | 1998-05-11 | Douglas I Buckley | GLP-1-analoger anvendelige ved diabetesbehandling |
KR100237148B1 (ko) | 1990-05-09 | 2000-01-15 | 한센 핀 베네드 | 엔도글루칸아제 효소를 함유하는 셀룰라제 제조물 |
DK36392D0 (da) | 1992-03-19 | 1992-03-19 | Novo Nordisk As | Anvendelse af kemisk forbindelse |
US5846747A (en) | 1992-03-25 | 1998-12-08 | Novo Nordisk A/S | Method for detecting glucagon-like peptide-1 antagonists and agonists |
DK39892D0 (da) | 1992-03-25 | 1992-03-25 | Bernard Thorens | Peptid |
US5424286A (en) | 1993-05-24 | 1995-06-13 | Eng; John | Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same |
WO1995005848A1 (en) | 1993-08-24 | 1995-03-02 | Novo Nordisk A/S | Protracted glp-1 |
ZA946881B (en) | 1993-09-07 | 1995-10-30 | Amylin Pharmaceuticals Inc | Methods for treating gastrointestinal motility |
US5705483A (en) | 1993-12-09 | 1998-01-06 | Eli Lilly And Company | Glucagon-like insulinotropic peptides, compositions and methods |
US5512549A (en) | 1994-10-18 | 1996-04-30 | Eli Lilly And Company | Glucagon-like insulinotropic peptide analogs, compositions, and methods of use |
US5523449A (en) | 1995-05-17 | 1996-06-04 | Bayer Corporation | Process for preparing phosphorodichlorido-dithioates by reacting alkylmercaptans with phosphorus trichloride in the presence of sulfur |
KR100600457B1 (ko) | 1996-06-05 | 2006-07-13 | 로셰 디아그노스틱스 게엠베하 | 엑센딘 유사체, 이의 제조방법 및 이를 함유한 약제 |
US6110703A (en) | 1996-07-05 | 2000-08-29 | Novo Nordisk A/S | Method for the production of polypeptides |
ATE493998T1 (de) | 1996-08-08 | 2011-01-15 | Amylin Pharmaceuticals Inc | Pharmazeutische zusammensetzung mit einem exendin-4-peptid |
US6268343B1 (en) | 1996-08-30 | 2001-07-31 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
DK0944648T3 (da) | 1996-08-30 | 2007-07-02 | Novo Nordisk As | GLP-1 derivater |
US6006753A (en) | 1996-08-30 | 1999-12-28 | Eli Lilly And Company | Use of GLP-1 or analogs to abolish catabolic changes after surgery |
US7235627B2 (en) | 1996-08-30 | 2007-06-26 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
US6277819B1 (en) | 1996-08-30 | 2001-08-21 | Eli Lilly And Company | Use of GLP-1 or analogs in treatment of myocardial infarction |
US6458924B2 (en) | 1996-08-30 | 2002-10-01 | Novo Nordisk A/S | Derivatives of GLP-1 analogs |
JP2001505872A (ja) | 1996-09-09 | 2001-05-08 | ジーランド ファーマシューティカルズ アクティーゼルスカブ | α―ヒドロキシ酸リンカーを含むペプチドプロドラッグ |
AU723268B2 (en) | 1996-09-09 | 2000-08-24 | Zealand Pharma A/S | Improved solid-phase peptide synthesis and agent for use in such synthesis |
UA65549C2 (uk) | 1996-11-05 | 2004-04-15 | Елі Ліллі Енд Компані | Спосіб регулювання ожиріння шляхом периферійного введення аналогів та похідних glp-1 (варіанти) та фармацевтична композиція |
AU5065198A (en) | 1996-11-15 | 1998-06-10 | Maria Grazia Masucci | Fusion proteins having increased half-lives |
DK1629849T4 (en) | 1997-01-07 | 2017-12-04 | Amylin Pharmaceuticals Llc | Pharmaceutical compositions comprising exedins and agonists thereof |
US6410511B2 (en) | 1997-01-08 | 2002-06-25 | Amylin Pharmaceuticals, Inc. | Formulations for amylin agonist peptides |
US6136784A (en) | 1997-01-08 | 2000-10-24 | Amylin Pharmaceuticals, Inc. | Amylin agonist pharmaceutical compositions containing insulin |
EP0981611A1 (en) | 1997-02-05 | 2000-03-01 | 1149336 Ontario Inc. | Polynucleotides encoding proexendin, and methods and uses thereof |
US5846937A (en) | 1997-03-03 | 1998-12-08 | 1149336 Ontario Inc. | Method of using exendin and GLP-1 to affect the central nervous system |
TR199903120T2 (xx) | 1997-05-07 | 2000-05-22 | Max-Planck-Gesellschaft Zur Förderung Der Wissenschaften | Yeni sistein türevleri, bunların üretimi için işlemler ve bunları ihtiva eden farmasötik maddeler. |
US7157555B1 (en) | 1997-08-08 | 2007-01-02 | Amylin Pharmaceuticals, Inc. | Exendin agonist compounds |
NZ502592A (en) | 1997-08-08 | 2002-03-28 | Amylin Pharmaceuticals Inc | Exendin agonist peptides and their use in the treatment of type I and II diabetes |
DE69838916T2 (de) | 1997-11-14 | 2008-12-18 | Amylin Pharmaceuticals, Inc., San Diego | Neuartige exendin agonisten |
US7223725B1 (en) | 1997-11-14 | 2007-05-29 | Amylin Pharmaceuticals, Inc. | Exendin agonist compounds |
JP2001523688A (ja) | 1997-11-14 | 2001-11-27 | アミリン・ファーマシューティカルズ,インコーポレイテッド | 新規エキセンジン・アゴニスト化合物 |
US7220721B1 (en) | 1997-11-14 | 2007-05-22 | Amylin Pharmaceuticals, Inc. | Exendin agonist peptides |
EP1049486A4 (en) | 1997-12-05 | 2006-01-04 | Lilly Co Eli | GLP-1 FORMULATIONS |
DE69936446T2 (de) | 1998-02-13 | 2008-03-06 | Amylin Pharmaceuticals, Inc., San Diego | Inotropische und diuretische effekte von exendin und glp-1 |
US6703359B1 (en) | 1998-02-13 | 2004-03-09 | Amylin Pharmaceuticals, Inc. | Inotropic and diuretic effects of exendin and GLP-1 |
EP1056775B1 (en) | 1998-02-27 | 2010-04-28 | Novo Nordisk A/S | Glp-1 derivatives of glp-1 and exendin with protracted profile of action |
ATE466028T1 (de) | 1998-02-27 | 2010-05-15 | Novo Nordisk As | N-terminal veränderte glp-1 abkömmlinge |
EP1950223A3 (en) | 1998-03-09 | 2009-05-13 | Zealand Pharma A/S | Pharmacologically active peptide conjugates having a reduced tendency towards enzymatic hydrolysis |
ATE269103T1 (de) | 1998-03-13 | 2004-07-15 | Novo Nordisk As | Stabilisierte wässerige glukagonlösungen enthaltend detergenzien |
WO1999049788A1 (en) | 1998-03-30 | 1999-10-07 | Focus Surgery, Inc. | Ablation system |
SE9802080D0 (sv) | 1998-06-11 | 1998-06-11 | Hellstroem | Pharmaceutical composition for the treatment of functional dyspepsia and/or irritable bowel syndrome and new use of substances therein |
WO2000009666A2 (en) | 1998-08-10 | 2000-02-24 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Differentiation of non-insulin producing cells into insulin producing cells by glp-1 or exendin-4 and uses thereof |
AU6294899A (en) | 1998-10-07 | 2000-04-26 | Medical College Of Georgia Research Institute, Inc. | Glucose-dependent insulinotropic peptide for use as an osteotropic hormone |
US6284725B1 (en) | 1998-10-08 | 2001-09-04 | Bionebraska, Inc. | Metabolic intervention with GLP-1 to improve the function of ischemic and reperfused tissue |
US7399489B2 (en) | 1999-01-14 | 2008-07-15 | Amylin Pharmaceuticals, Inc. | Exendin analog formulations |
DE60021166T3 (de) | 1999-01-14 | 2019-08-22 | Amylin Pharmaceuticals, Llc | Neue exendin agonist formulierungen und deren verabreichung |
US6872700B1 (en) | 1999-01-14 | 2005-03-29 | Amylin Pharmaceuticals, Inc. | Methods for glucagon suppression |
US6451987B1 (en) | 1999-03-15 | 2002-09-17 | Novo Nordisk A/S | Ion exchange chromatography of proteins and peptides |
RU2001128068A (ru) | 1999-03-17 | 2004-02-20 | Ново Нордиск А/С (DK) | Способ ацилирования пептидов и новые ацилирующие агенты |
US6451974B1 (en) | 1999-03-17 | 2002-09-17 | Novo Nordisk A/S | Method of acylating peptides and novel acylating agents |
US6271241B1 (en) | 1999-04-02 | 2001-08-07 | Neurogen Corporation | Cycloalkyl and aryl fused aminoalkyl-imidazole derivatives: modulators and GLP-1 receptors |
US6924264B1 (en) | 1999-04-30 | 2005-08-02 | Amylin Pharmaceuticals, Inc. | Modified exendins and exendin agonists |
JP2002544127A (ja) | 1999-04-30 | 2002-12-24 | アミリン・ファーマシューティカルズ,インコーポレイテッド | 修飾されたエキセンジンおよびエキセンジン・アゴニスト |
US6329336B1 (en) | 1999-05-17 | 2001-12-11 | Conjuchem, Inc. | Long lasting insulinotropic peptides |
US7601691B2 (en) | 1999-05-17 | 2009-10-13 | Conjuchem Biotechnologies Inc. | Anti-obesity agents |
US6506724B1 (en) | 1999-06-01 | 2003-01-14 | Amylin Pharmaceuticals, Inc. | Use of exendins and agonists thereof for the treatment of gestational diabetes mellitus |
US6344180B1 (en) | 1999-06-15 | 2002-02-05 | Bionebraska, Inc. | GLP-1 as a diagnostic test to determine β-cell function and the presence of the condition of IGT and type II diabetes |
EP1076066A1 (en) | 1999-07-12 | 2001-02-14 | Zealand Pharmaceuticals A/S | Peptides for lowering blood glucose levels |
US6528486B1 (en) | 1999-07-12 | 2003-03-04 | Zealand Pharma A/S | Peptide agonists of GLP-1 activity |
US6586438B2 (en) | 1999-11-03 | 2003-07-01 | Bristol-Myers Squibb Co. | Antidiabetic formulation and method |
JP4480329B2 (ja) | 2000-10-20 | 2010-06-16 | アミリン・ファーマシューティカルズ,インコーポレイテッド | Glp−1ペプチドによる冬眠心筋および糖尿病性心筋症の治療 |
GB0121709D0 (en) | 2001-09-07 | 2001-10-31 | Imp College Innovations Ltd | Food inhibition agent |
EP1837031B1 (en) * | 2002-06-07 | 2009-10-14 | Waratah Pharmaceuticals, Inc. | Compositions and methods for treating diabetes |
EP2028192A1 (en) | 2002-07-04 | 2009-02-25 | Zealand Pharma A/S | GLP-1 and methods for treating diabetes |
MXPA05003335A (es) | 2002-10-02 | 2005-07-05 | Zealand Pharma As | Compuestos de exendina-4 estabilizados. |
US7192922B2 (en) | 2002-11-19 | 2007-03-20 | Allegheny-Singer Research Institute | Method of treating left ventricular dysfunction |
US7623530B2 (en) | 2003-11-20 | 2009-11-24 | Nokia Corporation | Indication of service flow termination by network control to policy decision function |
CA2554458A1 (en) | 2004-01-30 | 2005-08-11 | Waratah Pharmaceuticals, Inc. | The combined use of glp-1 agonists and gastrin for regulating blood glucose levels |
US8076288B2 (en) | 2004-02-11 | 2011-12-13 | Amylin Pharmaceuticals, Inc. | Hybrid polypeptides having glucose lowering activity |
EP2422807A3 (en) * | 2004-02-11 | 2012-05-30 | Amylin Pharmaceuticals Inc. | Hybrid polypeptides with selectable properties |
TW200716159A (en) * | 2005-06-09 | 2007-05-01 | Univ Maryland | Method of use of antagonists of zonulin to prevent the loss of or to regenerate pancreatic cells |
WO2007095737A1 (en) * | 2006-02-21 | 2007-08-30 | Waratah Pharmaceuticals Inc. | Combination therapy for the treatment of diabetes comprising an exendin agonist and a gastrin compound |
JP5297817B2 (ja) | 2006-02-22 | 2013-09-25 | メルク・シャープ・アンド・ドーム・コーポレーション | オキシントモジュリン誘導体 |
EA023886B1 (ru) | 2006-11-08 | 2016-07-29 | Зеаланд Фарма А/С | Селективные аналоги глюкагонподобного пептида-2 (glp-2) |
WO2008071010A1 (en) | 2006-12-12 | 2008-06-19 | Waratah Pharmaceuticals Inc. | Combination treatments with selected growth/hormone regulatory factors for diabetes and related diseases |
TWI428346B (zh) | 2006-12-13 | 2014-03-01 | Imp Innovations Ltd | 新穎化合物及其等對進食行為影響 |
CA2677932A1 (en) | 2007-02-15 | 2008-08-21 | Indiana University Research And Technology Corporation | Glucagon/glp-1 receptor co-agonists |
EP2158214B1 (en) | 2007-06-15 | 2011-08-17 | Zealand Pharma A/S | Glucagon analogues |
FR2917552B1 (fr) | 2007-06-15 | 2009-08-28 | Sagem Defense Securite | Procede de regulation de la gigue de transmission au sein d'un terminal de reception |
GB2455553B (en) | 2007-12-14 | 2012-10-24 | Nuaire Ltd | Motor mounting assembly for an axial fan |
AU2009260301B2 (en) | 2008-06-17 | 2015-09-03 | Indiana University Research And Technology Corporation | Glucagon analogs exhibiting enhanced solubility and stability in physiological pH buffers |
NZ593813A (en) | 2008-12-15 | 2013-02-22 | Zealand Pharma As | Glucagon analogues |
MY160219A (en) | 2008-12-15 | 2017-02-28 | Zealand Pharma As | Glucagon analogues |
DK2370460T3 (da) | 2008-12-15 | 2014-08-04 | Zealand Pharma As | Glucagon analoger |
US8642541B2 (en) | 2008-12-15 | 2014-02-04 | Zealand Pharma A/S | Glucagon analogues |
WO2010096052A1 (en) | 2009-02-19 | 2010-08-26 | Merck Sharp & Dohme Corp. | Oxyntomodulin analogs |
US20110312881A1 (en) * | 2009-12-21 | 2011-12-22 | Amunix, Inc. | Bifunctional polypeptide compositions and methods for treatment of metabolic and cardiovascular diseases |
AU2011206979B2 (en) | 2010-01-20 | 2015-09-10 | Zealand Pharma A/S | Treatment of cardiac conditions |
JP5969461B2 (ja) | 2010-04-27 | 2016-08-17 | ジーランド ファーマ アクティーゼルスカブ | Glp−1受容体作動薬とガストリンとのペプチド複合体及びその使用 |
WO2013064669A1 (en) | 2011-11-03 | 2013-05-10 | Zealand Pharma A/S | Glp-1 receptor agonist peptide gastrin conjugates |
TWI608013B (zh) | 2012-09-17 | 2017-12-11 | 西蘭製藥公司 | 升糖素類似物 |
US9988429B2 (en) | 2013-10-17 | 2018-06-05 | Zealand Pharma A/S | Glucagon analogues |
KR102569036B1 (ko) | 2013-10-17 | 2023-08-23 | 질랜드 파마 에이/에스 | 아실화된 글루카곤 유사체 |
-
2012
- 2012-11-02 WO PCT/EP2012/071766 patent/WO2013064669A1/en active Application Filing
- 2012-11-02 CN CN201280060332.8A patent/CN104144704B/zh active Active
- 2012-11-02 US US14/355,906 patent/US9259477B2/en active Active
- 2012-11-02 JP JP2014539352A patent/JP6359972B2/ja active Active
- 2012-11-02 KR KR1020147015223A patent/KR20140100947A/ko not_active Application Discontinuation
- 2012-11-02 EA EA201490790A patent/EA028951B9/ru not_active IP Right Cessation
- 2012-11-02 MX MX2014005351A patent/MX2014005351A/es unknown
- 2012-11-02 CA CA2853884A patent/CA2853884A1/en not_active Abandoned
- 2012-11-02 AR ARP120104123A patent/AR088636A1/es unknown
- 2012-11-02 BR BR112014010780A patent/BR112014010780A2/pt not_active Application Discontinuation
- 2012-11-02 TW TW101140873A patent/TW201326194A/zh unknown
- 2012-11-02 EP EP12783582.5A patent/EP2773377B1/en active Active
- 2012-11-02 AU AU2012331053A patent/AU2012331053A1/en not_active Abandoned
-
2015
- 2015-09-24 US US14/864,540 patent/US9861706B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
CN104144704A (zh) | 2014-11-12 |
WO2013064669A1 (en) | 2013-05-10 |
CA2853884A1 (en) | 2013-05-10 |
US20140336107A1 (en) | 2014-11-13 |
EA201490790A1 (ru) | 2014-10-30 |
KR20140100947A (ko) | 2014-08-18 |
US9861706B2 (en) | 2018-01-09 |
US9259477B2 (en) | 2016-02-16 |
JP6359972B2 (ja) | 2018-07-18 |
MX2014005351A (es) | 2014-05-28 |
AU2012331053A1 (en) | 2014-05-29 |
AR088636A1 (es) | 2014-06-25 |
EA028951B9 (ru) | 2018-05-31 |
CN104144704B (zh) | 2018-03-23 |
EP2773377B1 (en) | 2020-07-08 |
US20160082118A1 (en) | 2016-03-24 |
EP2773377A1 (en) | 2014-09-10 |
EA028951B1 (ru) | 2018-01-31 |
JP2015502918A (ja) | 2015-01-29 |
BR112014010780A2 (pt) | 2017-04-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10406207B2 (en) | Peptide conjugates of GLP-1 receptor agonists and gastrin and their use | |
US9861706B2 (en) | GLP-1 receptor agonist peptide gastrin conjugates | |
KR102310389B1 (ko) | Gip-glp-1 이원 효능제 화합물 및 방법 | |
AU2016232218B2 (en) | Amylin analogues | |
TW201811818A (zh) | 澱粉素類似物 | |
TW201542588A (zh) | 糊精類似物 | |
WO2013098408A1 (en) | Glucagon and cck receptor agonist peptide conjugates |