CN116514952A - 一类glp-1类似物及其应用 - Google Patents
一类glp-1类似物及其应用 Download PDFInfo
- Publication number
- CN116514952A CN116514952A CN202310681999.XA CN202310681999A CN116514952A CN 116514952 A CN116514952 A CN 116514952A CN 202310681999 A CN202310681999 A CN 202310681999A CN 116514952 A CN116514952 A CN 116514952A
- Authority
- CN
- China
- Prior art keywords
- glp
- seq
- analogue
- acid
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 title claims abstract description 49
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 14
- 208000008589 Obesity Diseases 0.000 claims abstract description 12
- 235000020824 obesity Nutrition 0.000 claims abstract description 12
- 208000032928 Dyslipidaemia Diseases 0.000 claims abstract description 11
- 208000017170 Lipid metabolism disease Diseases 0.000 claims abstract description 11
- 150000001413 amino acids Chemical group 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 41
- 208000030159 metabolic disease Diseases 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- 208000016097 disease of metabolism Diseases 0.000 claims description 3
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims description 2
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 claims description 2
- 239000005639 Lauric acid Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 229930016911 cinnamic acid Natural products 0.000 claims description 2
- 235000013985 cinnamic acid Nutrition 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 235000011044 succinic acid Nutrition 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000002632 lipids Chemical class 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 8
- 230000001270 agonistic effect Effects 0.000 abstract description 7
- 230000001603 reducing effect Effects 0.000 abstract description 6
- 101001015516 Homo sapiens Glucagon-like peptide 1 receptor Proteins 0.000 abstract description 5
- 208000001145 Metabolic Syndrome Diseases 0.000 abstract description 4
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 241000270934 Rana catesbeiana Species 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 70
- 229920001184 polypeptide Polymers 0.000 description 57
- 102000004196 processed proteins & peptides Human genes 0.000 description 57
- 239000011347 resin Substances 0.000 description 30
- 229920005989 resin Polymers 0.000 description 30
- 241000699670 Mus sp. Species 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 230000000694 effects Effects 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 125000006239 protecting group Chemical group 0.000 description 13
- DLSWIYLPEUIQAV-UHFFFAOYSA-N Semaglutide Chemical compound CCC(C)C(NC(=O)C(Cc1ccccc1)NC(=O)C(CCC(O)=O)NC(=O)C(CCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CCC(NC(=O)CCCCCCCCCCCCCCCCC(O)=O)C(O)=O)NC(=O)C(C)NC(=O)C(C)NC(=O)C(CCC(N)=O)NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(CC(C)C)NC(=O)C(Cc1ccc(O)cc1)NC(=O)C(CO)NC(=O)C(CO)NC(=O)C(NC(=O)C(CC(O)=O)NC(=O)C(CO)NC(=O)C(NC(=O)C(Cc1ccccc1)NC(=O)C(NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(C)(C)NC(=O)C(N)Cc1cnc[nH]1)C(C)O)C(C)O)C(C)C)C(=O)NC(C)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CCCNC(N)=N)C(=O)NCC(O)=O DLSWIYLPEUIQAV-UHFFFAOYSA-N 0.000 description 12
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 12
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 11
- 102100040918 Pro-glucagon Human genes 0.000 description 11
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 10
- 230000002218 hypoglycaemic effect Effects 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 108010060325 semaglutide Proteins 0.000 description 10
- 229950011186 semaglutide Drugs 0.000 description 10
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 10
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 9
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 8
- 238000001308 synthesis method Methods 0.000 description 8
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 235000012000 cholesterol Nutrition 0.000 description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 4
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 4
- 108090001061 Insulin Proteins 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- CMWYAOXYQATXSI-UHFFFAOYSA-N n,n-dimethylformamide;piperidine Chemical compound CN(C)C=O.C1CCNCC1 CMWYAOXYQATXSI-UHFFFAOYSA-N 0.000 description 4
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 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 3
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108010019598 Liraglutide Proteins 0.000 description 3
- 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 3
- 241000700159 Rattus Species 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 229960002701 liraglutide Drugs 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- QWXZOFZKSQXPDC-NSHDSACASA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C)C(O)=O)C3=CC=CC=C3C2=C1 QWXZOFZKSQXPDC-NSHDSACASA-N 0.000 description 2
- IXHPIPUIOSSAIS-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]imidazol-4-yl]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CN(C(=O)OC(C)(C)C)C=N1 IXHPIPUIOSSAIS-NSHDSACASA-N 0.000 description 2
- XQPYRJIMPDBGRW-UHFFFAOYSA-N 2-[2-[2-(9h-fluoren-9-ylmethoxycarbonylamino)ethoxy]ethoxy]acetic acid Chemical compound C1=CC=C2C(COC(=O)NCCOCCOCC(=O)O)C3=CC=CC=C3C2=C1 XQPYRJIMPDBGRW-UHFFFAOYSA-N 0.000 description 2
- JDDWRLPTKIOUOF-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl n-[[4-[2-[bis(4-methylphenyl)methylamino]-2-oxoethoxy]phenyl]-(2,4-dimethoxyphenyl)methyl]carbamate Chemical compound COC1=CC(OC)=CC=C1C(C=1C=CC(OCC(=O)NC(C=2C=CC(C)=CC=2)C=2C=CC(C)=CC=2)=CC=1)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JDDWRLPTKIOUOF-UHFFFAOYSA-N 0.000 description 2
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- 102000051325 Glucagon Human genes 0.000 description 2
- 108060003199 Glucagon Proteins 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- 238000010162 Tukey test Methods 0.000 description 2
- 230000008484 agonism Effects 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- LUFPJJNWMYZRQE-UHFFFAOYSA-N benzylsulfanylmethylbenzene Chemical compound C=1C=CC=CC=1CSCC1=CC=CC=C1 LUFPJJNWMYZRQE-UHFFFAOYSA-N 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000002173 cutting fluid Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 208000004104 gestational diabetes Diseases 0.000 description 2
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 2
- 229960004666 glucagon Drugs 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000012982 microporous membrane Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 235000020925 non fasting Nutrition 0.000 description 2
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- 230000010355 oscillation Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 239000013585 weight reducing agent Substances 0.000 description 2
- OJBNDXHENJDCBA-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-(prop-2-enoxycarbonylamino)hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OCC=C)C(=O)O)C3=CC=CC=C3C2=C1 OJBNDXHENJDCBA-QFIPXVFZSA-N 0.000 description 1
- YPTNAIDIXCOZAJ-LHEWISCISA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[[(4-methylphenyl)-diphenylmethyl]amino]hexanoic acid Chemical compound C1=CC(C)=CC=C1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)NCCCC[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 YPTNAIDIXCOZAJ-LHEWISCISA-N 0.000 description 1
- WDUQJXKBWRNMKI-UHFFFAOYSA-N 18-[(2-methylpropan-2-yl)oxy]-18-oxooctadecanoic acid Chemical compound CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(O)=O WDUQJXKBWRNMKI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 1
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101000788682 Homo sapiens GATA-type zinc finger protein 1 Proteins 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
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 238000013295 T2DM animal model Methods 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- -1 fmoc-Lys (Dde) -OH Chemical compound 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 210000005159 islet delta cell Anatomy 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000013227 male C57BL/6J mice Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 229940127209 oral hypoglycaemic agent Drugs 0.000 description 1
- 229940125395 oral insulin Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003076 paracrine Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 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 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/605—Glucagons
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Diabetes (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Emergency Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Child & Adolescent Psychology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明提供了一类GLP‑1类似物及其应用,所述的GLP‑1类似物的氨基酸序列为SEQ ID NO:1‑SEQ ID NO:6、SEQ ID NO:8‑SEQ ID NO:10中的序列之一。该GLP‑1类似物对人GLP‑1受体有强激动活性且稳定性高,具有一天一次或一周一次给药的药代动力学特征。本发明是基于牛蛙GLP‑1序列设计的变体,在保留GLP‑1类似物对糖尿病的治疗作用同时还具有优异的减重和降脂效果;将其应用于制备治疗代谢综合征,诸如糖尿病、肥胖症、血脂障碍等疾病药物方面具有更大的潜力。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及一类GLP-1类似物及其应用。
背景技术
糖尿病(Diabetes mellitus,DM)是一组由遗传和环境等多种病因引起以慢性高血糖为特征的代谢性疾病群。由于胰岛素分泌相对或绝对不足;或胰岛素作用缺陷引起糖、蛋白质、脂肪、水和电解质等一系列代谢紊乱。持续高血糖是基本特征。久病可引起多系统损害,导致眼、肾、神经及心脑血管、下肢等器官的慢性并发症。糖尿病分1型糖尿病(T1DM)、2型糖尿病(T2DM)、妊娠期糖尿病和其他特殊类型糖尿病。研究发现T2DM患者占90%以上。目前糖尿病的治疗方法主要包括口服降糖药物和胰岛素治疗,但这些方法在长期的治疗中会产生毒副作用。
胰高血糖素样肽-1(Glucagon-Like Peptide-1,GLP-1)具有保护β细胞的作用,GLP-1可作用于胰岛β细胞,促进胰岛素基因的转录、胰岛素的合成和分泌,并可刺激胰岛β细胞的增殖和分化,抑制胰岛β细胞凋亡,增加胰岛β细胞数量。此外,GLP-1还可作用于胰岛α细胞,强烈地抑制胰高血糖素的释放,并作用于胰岛δ细胞,促进生长抑素的分泌,生长抑素又可作为旁分泌激素参与抑制胰高血糖素的分泌。研究证明,GLP-1可通过多种机制明显地改善T2DM动物模型或患者的血糖情况,其中促进胰岛β细胞的再生和修复,增加胰岛β细胞数量的作用尤为显著,这为T2DM的治疗提供了一个非常好的前景。然而天然GLP-1存在局限性,即它的半衰期特别短,分泌2~3分钟后就会被二肽基肽酶(DPP-IV)降解,即使外源性给予GLP-1,也同样很快会被DPP-IV降解。另外,内源性GLP-1还会被肾脏快速滤过代谢,其体内半衰期仅为2-3min。因此,需要我们寻找和GLP-1具有相似的生物活性,但能在体内长效作用的新型GLP-1受体激动剂。
肥胖及其相关代谢综合征已成为全球性的公众健康问题,许多代谢综合征如2型糖尿病(T2DM)、非酒精性脂肪肝病(NAFLD)、非酒精性脂肪肝炎(NASH)、血脂代谢异常的发病率与病程发展都与肥胖密切相关。GLP-1可以抑制食欲、延缓胃排空实现降低体重的作用。虽然GLP-1具有优异的降糖作用和一定的减重效果,但是其减重作用仍然较为有限,并且其调脂作用也较弱。因此,对肥胖和糖尿病患者来说,仍然需要更为安全耐受的,可有效减轻体重、控制血糖和能有效调脂的新型GLP-1类似物。
发明内容
本发明的目的是提供一类GLP-1类似物及其应用,该GLP-1类似物可对人GLP-1受体有强激动活性且稳定性高,可具有一天一次或一周一次给药的药代动力学特征,对糖尿病的治疗作用同时可具有优异的减重和降脂效果;将其应用于制备治疗代谢综合征,诸如糖尿病、肥胖症、血脂障碍等疾病药物方面具有更大的潜力。
为实现上述发明目的,本发明的技术方案具体如下:
一类GLP-1类似物,所述GLP-1类似物的氨基酸序列为下列序列之一:
(1)SEQ ID NO:1
(2)SEQ ID NO:2
(3)SEQ ID NO:3
(4)SEQ ID NO:4
(5)SEQ ID NO:5
(6)SEQ ID NO:6
(7)SEQ ID NO:7
(8)SEQ ID NO:8
(9)SEQ ID NO:9
(10)SEQ ID NO:10
本发明还提供了一类GLP-1类似物药学上可接受的盐。
优选的,所述盐为GLP-1类似物与下述化合物中的一种所形成的盐:盐酸、乙酸、水杨酸、月桂酸、肉桂酸、柠檬酸草酸、乳酸、琥珀酸。
本发明还提供了一类GLP-1类似物所制备的药剂,所述药剂是任何一种药剂学上所述的片剂、胶囊、吸入剂、喷雾剂、注射剂、膜剂、贴剂、乳剂或者复方制剂,药剂由一类GLP-1类似物和药学上可接受的药用辅料、载体或稀释剂组成。
本发明还提供了含有一类GLP-1类似物的药物组合物,该药物组合物以上述任一GLP-1类似物为有效原料,或者其药学上可接受的盐为有效原料,再加上药学上可接受的载体或稀释剂组成。
本发明还提供了本发明所述的GLP-1类似物或其药学上可接受的盐、或其药物组合物或其药剂在制备用于治疗代谢性疾病或病症的药物中的用途。在特定方面,代谢性疾病或病症为糖尿病、肥胖症、血脂障碍。在特定方面,糖尿病为T1DM、T2DM或妊娠糖尿病。在特定方面,所述药物用于治疗超过一种代谢疾病或病症,例如,糖尿病和肥胖;肥胖和血脂障碍;糖尿病和血脂障碍;糖尿病、血脂障碍和肥胖。
与现有技术相比,本发明的有益效果:
本发明提供的一类GLP-1类似物是基于牛蛙GLP-1序列设计的变体,在保留GLP-1类似物对糖尿病的治疗作用同时具有意想不到的优异的减重和降脂效果,相较于已上市的GLP-1类药物,本发明提供的GLP-1类似物具有更好的降糖效果和显著提高的减重和降脂作用,在糖尿病、肥胖症、血脂障碍等疾病的治疗方面更具潜力。另外,本发明提供的GLP-1类似物对人GLP-1受体有强激动活性且化学性质稳定,具有支持一天一次或一周一次给药的药代动力学特征。本发明提供的GLP-1类似物对T2DM、肥胖、血脂障碍等代谢性疾病的治疗作用显著优于现有上市药物。因此,本发明提供的GLP-1类似物适合作为治疗代谢性疾病(如糖尿病、肥胖症、血脂障碍等)药物的活性成分。
附图说明
图1显示的是各受试物单次给药在ICR小鼠上的急性降血糖作用结果示意图;
图2显示的是各受试物单次给药在db/db小鼠上的长效降血糖作用结果示意图;
图3显示的是各受试物在DIO小鼠长期给药21天的体重变化百分比结果示意图。
具体实施方式
以下结合附图和具体实施例对本发明作进一步详细说明。
除非本文另有定义,否则本申请书中所使用的科学和技术术语应具有本领域普通技术人员通常理解的含义。通常,本文所述的与化学、生物学、药理学关联使用的术语和方法是本领域中公知和常用的。
另外,本发明体积的氨基酸根据IUPAC-IUB的命名规则缩写如下:
丙氨酸(Ala,A);精氨酸(Arg,R);天冬酰胺(Asn,N);天冬氨酸(Asp,D);半胱氨酸(Cys,C);谷氨酸(Glu,E);谷氨酰胺(Gln,Q);甘氨酸(Gly,G);组氨酸(His,H);异亮氨酸(Ile,I);亮氨酸(Leu,L);赖氨酸(Lys,K);甲硫氨酸(Met,M);苯丙氨酸(Phe,F);脯氨酸(Pro,P);丝氨酸(Ser,S);苏氨酸(Thr,T);色氨酸(Trp,W);酪氨酸(Tyr,Y);缬氨酸(Val,V)。
另外,除非明确标明,本发明的多肽化合物中的所有氨基酸残基优选为L构型。
另外,所述序列的C端上的“-NH2”部分表明C端上的酰胺基(-CONH2)。
另外,本发明序列中除了天然氨基酸以外,还使用了非天然氨基酸α-氨基异丁酸(Aib)。
本发明是通过下列实施例来进行说明的,但这些实施例不做任何限制本发明权利的解释。
实施例1
SEQ ID NO:1多肽化合物的合成
(1)树脂的溶胀
称取担载量为0.36mmol/g的RinkAmide MBHA树脂0.278g(0.1mmol当量),放入25mL的反应器中,用7mL的DCM和甲醇交替清洗树脂1次,7mL的DCM清洗树脂2次,然后用7mL的DCM溶胀树脂1h,最后用7mLDMF清洗树脂3次。
(2)树脂Fmoc保护基的脱除
将溶胀后的树脂转入PSI-200多肽合成仪,加入7mL 20%哌啶/DMF(v/v)室温反应5min,滤去脱保护溶液,7mLDMF清洗树脂一次,再加入7mL 20%哌啶/DMF(v/v)脱保护溶剂与树脂反应15min,最后7mL DMF清洗树脂4次,每次2min,得到脱除Fmoc保护基的Rink树脂。
(3)Fmoc-Ala-Rink amide-MBHAResin的合成
称Fmoc-Ala-OH(0.4mmol),用2mLDMF溶解,加入3mL DIC/HOBt(0.4mmol/0.44mmol)缩合剂,加入反应器中,室温震荡反应2h,滤去反应液后用7mL DMF清洗树脂4次,使用Kaiser试剂检测反应耦合是否完全,如不完全则2次耦合。
(4)肽链的延长
按照肽链的序列,重复上述脱保护和耦合的步骤依次连接上相应的氨基酸,直至肽链合成完毕。其中侧链修饰位点的Lys采用Fmoc-Lys(Dde)-OH保护策略,同时N末端的His使用的是Boc-His(Boc)-OH。
(5)Lys侧链的修饰
肽链合成完毕后,加入7mL 2%水合肼/DMF(v/v)选择性脱除Lys的Dde保护基,Dde保护基脱除后加入0.4mmol的Fmoc-Glu-OtBu,0.4mmol的DIC及0.44mmol的HOBt,震荡反应2h。脱除Fmoc保护基后,再次加入0.4mmol的Fmoc-Glu-OtBu,0.4mmol的DIC及0.44mmol的HOBt,震荡反应2h。脱除Fmoc保护基后,加入0.4mmol的棕榈酸,0.4mmol的DIC及0.44mmol的HOBt缩合反应2h,反应完全后用7mLDMF清洗树脂4次。
(6)多肽的裂解
将上述得到的连有多肽的树脂转移至圆底瓶中,使用切割剂Reagent R(TFA/苯甲硫醚/苯酚/EDT,90:5:3:2,V/V)5mL切割树脂,在油浴中恒温30℃反应2h,切割液倾入40mL冰乙醚中,冷冻离心后粗品用15mL冰乙醚洗涤3次,最后用氮气吹干得到粗肽。
(7)多肽的纯化和表征
将目标多肽粗品溶于水中,用0.25μm微孔滤膜过滤后进岛津制备型反相HPLC系统纯化。色谱条件为C18反相制备柱(250mm×20mm,12μm);流动相A:0.1%TFA/水(V/V),流动相B:甲醇(V/V);流速为8mL/min;检测波长为214nm。采用线性梯度(20%B~70%B/30min)洗脱,收集目标峰,除去甲醇后冻干得纯品0.10g,纯度大于98%,通过LC-MS确认目标多肽的分子量。理论相对分子质量为3982.6。ESI-MS m/z:计算值[M+3H]3+1328.5,[M+4H]4+996.6;观察值[M+3H]3+1328.0,[M+4H]4+996.3。
实施例2
SEQ ID NO:2多肽化合物的合成
合成方法同实施例1,收集目标峰冻干得纯品0.11g,纯度大于98%,通过MS确认目标多肽的分子量。理论相对分子质量为3983.5。ESI-MS m/z:计算值[M+3H]3+1328.8,[M+4H]4+996.9;观察值[M+3H]3+1328.3,[M+4H]4+996.5。
实施例3
SEQ ID NO:3多肽化合物的合成
合成方法同实施例1,收集目标峰冻干得纯品0.09g,纯度大于98%,通过MS确认目标多肽的分子量。理论相对分子质量为3982.6。ESI-MS m/z:计算值[M+3H]3+1328.5,[M+4H]4+996.6;观察值[M+3H]3+1328.0,[M+4H]4+996.3。
实施例4
SEQ ID NO:4多肽化合物的合成
合成方法同实施例1,收集目标峰冻干得纯品0.10g,纯度大于98%,通过MS确认目标多肽的分子量。理论相对分子质量为3814.4。ESI-MS m/z:计算值[M+3H]3+1272.5,[M+4H]4+954.6;观察值[M+3H]3+1272.0,[M+4H]4+954.2。
实施例5
SEQ ID NO:5多肽化合物的合成
合成方法同实施例1,收集目标峰冻干得纯品0.11g,纯度大于98%,通过MS确认目标多肽的分子量。理论相对分子质量为3815.3。ESI-MS m/z:计算值[M+3H]3+1272.8,[M+4H]4+954.8;观察值[M+3H]3+1272.3,[M+4H]4+954.5。
实施例6
SEQ ID NO:6多肽化合物的合成
(1)树脂的溶胀
称取担载量为0.382mmol/g的RinkAmide MBHA树脂0.262g(0.1mmol当量),放入25mL的反应器中,用7mL的DCM和甲醇交替清洗树脂1次,7mL的DCM清洗树脂2次,然后用7mL的DCM溶胀树脂1h,最后用7mLDMF清洗树脂3次。
(2)树脂Fmoc保护基的脱除
将溶胀后的树脂转入PSI-200多肽合成仪,加入7mL 20%哌啶/DMF(v/v)室温反应5min,滤去脱保护溶液,7mLDMF清洗树脂一次,再加入7mL 20%哌啶/DMF(v/v)脱保护溶剂与树脂反应15min,最后7mLDMF清洗树脂4次,每次1.5min,得到脱除Fmoc保护基的Rink树脂。
(3)Fmoc-Ala-Rink amide-MBHAResin的合成
称Fmoc-Ala-OH(0.4mmol),用3mL 10%DMF/DMSO(v/v)溶解,加入2ml DIC/HOBt(0.4mmol/0.44mmol)缩合剂,预活化30min后,将活化好的氨基酸加入反应器中,室温震荡反应2h,滤去反应液后用7mLDMF清洗树脂4次,使用Kaiser试剂检测反应耦合是否完全,如不完全则2次耦合。
(4)肽链的延长
按照肽链的序列,重复上述脱保护和耦合的步骤依次连接上相应的氨基酸,直至肽链合成完毕。其中12位Lys可以采用Fmoc-Lys(Alloc)-OH、Fmoc-Lys(Dde)-OH、Fmoc-Lys(Mtt)-OH或Fmoc-Lys(ivDde)-OH等。本实例中采用Fmoc-Lys(Dde)-OH保护策略,同时N末端的His使用的是Boc-His(Boc)-OH。
(5)Lys侧链的修饰
肽链合成完毕后,加入7mL 2%水合肼/DMF(v/v)选择性脱除12位Lys的Dde保护基,Dde保护基脱除后加入0.4mmol的Fmoc-AEEA-OH,0.4mmol的DIC及0.44mmol的HOBt,震荡缩合反应2h。脱除Fmoc保护基后,再次加入0.4mmol的Fmoc-AEEA-OH,0.4mmol的DIC及0.44mmol的HOBt,震荡缩合反应2h。脱除Fmoc保护基后,加入0.4mmol的Fmoc-Glu-OtBu,0.4mmol的DIC及0.44mmol的HOBt,震荡缩合反应2h。脱除Fmoc保护基后,加入0.4mmol的十八烷二酸单叔丁酯,0.4mmol的DIC及0.44mmol的HOBt缩合反应2h,反应完全后用7mLDMF清洗树脂4次。
(6)多肽的裂解
将上述得到的连有多肽的树脂转移至圆底瓶中,使用切割剂Reagent R(TFA/苯甲硫醚/苯酚/EDT,90:5:3:2,V/V)5mL切割树脂,在油浴中恒温30℃反应2h,切割液倾入40mL冰乙醚中,冷冻离心后粗品用15mL冰乙醚洗涤3次,最后用氮气吹干得到粗肽。
(7)多肽的纯化和表征
将目标多肽粗品溶于水中,用0.25μm微孔滤膜过滤后进岛津制备型反相HPLC系统纯化。色谱条件为C18反相制备柱(250mm×20mm,12μm);流动相A:0.1%TFA/水(V/V),流动相B:甲醇(V/V);流速为8mL/min;检测波长为214nm。采用线性梯度(20%B~80%B/30min)洗脱,收集目标峰,除去甲醇后冻干得纯品0.11g,纯度大于98%,通过LC-MS确认目标多肽的分子量。理论相对分子质量为4330.9。ESI-MS m/z:计算值[M+3H]3+1444.6,[M+4H]4+1083.7;观察值[M+3H]3+1444.1,[M+4H]4+1083.3。
实施例7
SEQ ID NO:7多肽化合物的合成
合成方法同实施例6,收集目标峰冻干得纯品0.12g,纯度大于98%,通过MS确认目标多肽的分子量。理论相对分子质量为4331.9。ESI-MS m/z:计算值[M+3H]3+1445.0,[M+4H]4+1084.0;观察值[M+3H]3+1444.4,[M+4H]4+1083.5。
实施例8
SEQ ID NO:8多肽化合物的合成
合成方法同实施例6,收集目标峰冻干得纯品0.12g,纯度大于98%,通过MS确认目标多肽的分子量。理论相对分子质量为4330.9。ESI-MS m/z:计算值[M+3H]3+1444.6,[M+4H]4+1083.7;观察值[M+3H]3+1444.1,[M+4H]4+1083.3。
实施例9
SEQ ID NO:9多肽化合物的合成
合成方法同实施例6,收集目标峰冻干得纯品0.11g,纯度大于98%,通过MS确认目标多肽的分子量。理论相对分子质量为4162.7。ESI-MS m/z:计算值[M+3H]3+1388.6,[M+4H]4+1041.7;观察值[M+3H]3+1388.0,[M+4H]4+1041.3。
实施例10
SEQ ID NO:10多肽化合物的合成
合成方法同实施例6,收集目标峰冻干得纯品0.12g,纯度大于98%,通过MS确认目标多肽的分子量。理论相对分子质量为4163.7。ESI-MS m/z:计算值[M+3H]3+1388.9,[M+4H]4+1041.9;观察值[M+3H]3+1388.4,[M+4H]4+1041.5。
实施例11
多肽化合物对人GLP-1受体的激动活性测定
通过功能测定法来确定多肽化合物对受体的激动作用,GLP-1受体激动活性通过测量稳定表达人GLP-1受体的HEK-293细胞系的cAMP响应。将稳定表达GLP-1受体的细胞分入T175培养瓶并在培养基(DMEM/10%FBS)中过夜生长至接近汇合状态,然后除去培养基,并用无钙和镁的PBS洗涤细胞,然后用Accutase酶进行蛋白酶处理。洗涤脱离的细胞并将其重悬于测定缓冲液(20mM HEPES,0.1%BSA,2mM IBMX,1×HBSS)中,并确定细胞密度,并将25μL的等分试样分装至96孔板的孔中。为了测量,将25μL的测试多肽化合物在测定缓冲液中的溶液添加到孔中,然后室温温育30分钟。用Cisbio的试剂盒,基于均相时间分辨荧光(HTRF)来确定细胞的cAMP含量。添加稀释于裂解缓冲液(试剂盒组分)中的HTRF试剂后,将平板温育30分钟,然后测量665/620nm处的荧光比。通过检测引起最大响应的50%激活的浓度(EC50)来对激动剂的体外效力进行量化。
将本专利申请实施例中的检测数据(nM)显示于下表1中,虽然用一定数量的有效数字来陈述检测数据,但不应该认为表示数据已确定精确为有效数字的数。
表1:多肽化合物对人GLP-1受体的激动活性
如表1所示,所有多肽化合物都显示出了对GLP-1受体的强激动活性,同时,所有多肽化合物都显示出了比GLP-1更好的GLP-1受体激动活性。
实施例12
多肽化合物的溶解度和稳定性测试
在测试多肽化合物的溶解度和稳定性之前,首先使用HPLC确定其纯度。然后,基于确定的%纯度,在不同的缓冲体系中,溶解10mg多肽化合物在1mL溶液中,温和搅拌2小时。使用4500rpm离心20分钟后,取上清液进HPLC分析,确定峰面积。然后与相应样品标准溶液比对,计算得到受试样品溶液的相对浓度。对于稳定性测试,将溶解度获得的上清液的等分试样在40℃储存7天,然后样品在4500rpm离心20分钟,上清液进HPLC分析,确定峰面积。通过比较稳定性实验开始前的峰面积(t0)和存储7天后的峰面积(t7),得到“%剩余肽”。按以下公式计算:%剩余肽=[(峰面积t7)×100]/峰面积t0,稳定性表示为“%剩余肽”,计算结果如下表2所示。
表2:多肽化合物的溶解度和稳定性
如表2结果显示,本发明的多肽化合物与天然GLP-1相比,在机体可接受的注射液pH条件下的溶解性大幅改善,具备了有利于制剂的特性。此外,在pH 4.5和中性pH条件下本发明的多肽化合物也具有很高的稳定性。
实施例13
多肽化合物在大鼠体内的药代动力学性质
SD大鼠给予50nmol/kg的liraglutide、semaglutide、SEQ ID NO:2和SEQ ID NO:7皮下(s.c.)注射给药,在给药后0.25h、0.5h、1h、2h、4h、8h、16h、24h和48h收集血样。使用乙腈沉淀蛋白质后,用LC-MS分析血浆样品。用WinonLin 5.2.1(非房室模型)计算药代参数和半衰期(表3)。
表3:多肽化合物在大鼠体内的药代动力学概貌
样品 | T1/2(h) | Cmax(ng/mL) |
Liraglutide | 2.3 | 489 |
Semaglutide | 9.2 | 519 |
SEQ ID NO:2 | 5.0 | 452 |
SEQ ID NO:7 | 13.3 | 429 |
如表3结果显示,本发明的多肽化合物的体内半衰期显著延长,优于liraglutide或semaglutide,具有支持每天一次给药或每周一次给药的药代动力学特征。
实施例14
多肽化合物在小鼠体内急性降血糖活性
雄性ICR小鼠,随机分组,每组6只。只给饮水,禁食过夜。空白组腹腔注射给予生理盐水(10mg/kg),给药组分为3组,小鼠非空腹状态下分别腹腔单次注射30nmol/kg的semaglutide、SEQ ID NO:2和SEQ ID NO:7。30分钟后,各组小鼠腹腔给予3g/kg的葡萄糖溶液。在-30min、0min、15min、30min、60min、120min用血糖仪测定血糖水平。
如图1结果所示,在ICR小鼠体内的急性降糖实验表明,SEQ ID NO:2和SEQ ID NO:7多肽化合物显著的提高了小鼠的糖耐量水平,具有优异的降血糖作用,它们的降血糖作用还明显优于semaglutide。
实施例15
多肽化合物在小鼠体内长效降血糖活性
雄性db/db小鼠,随机分组,每组6只。空白组皮下注射给予生理盐水(10mg/kg),给药组分为2组,小鼠实验期间自由进食和饮水,小鼠非空腹状态下分别皮下单次注射30nmol/kg的semaglutide和SEQ ID NO:7。在给药前0h,以及给药后4h、6h、24h、48h和72h用血糖仪测量各组小鼠血糖水平。
如图2结果所示,在db/db小鼠体内的降血糖实验结果表明,本发明的多肽化合物显示出了明显优于阳性对照药semaglutide的长效降血糖活性。
实施例16
多肽化合物对饮食诱导肥胖(DIO)小鼠血酯和体重的影响
雄性C57BL/6J小鼠,体重22g左右,用Research Diets公司的D12492高脂饲料饲养18周造DIO小鼠模型。在给药开始前,各组DIO小鼠按照体重随机分组,共分为4组,每组6只,分别为生理盐水组(空白对照组)、阳性对照组(semaglutide)和受试样品组(SEQ ID NO:2和SEQ ID NO:7)。各组小鼠每两天一次皮下注射生理盐水(10mg/kg),semaglutide(30nmol/kg),SEQ ID NO:7(30nmol/kg),每天一次注射SEQ ID NO:2(30nmol/kg),给药周期21天。每天记录小鼠体重变化。在实验结束后,各组小鼠处死,取血制血清,取肝脏制匀浆,并测量肝脏和血清的甘油三酯(TG)和总胆固醇(TC)含量。
如图3结果显示,本发明的多肽化合物SEQ ID NO:2和SEQ ID NO:7在30nmol/kg的剂量下,在DIO小鼠体内连续给药3周,分别可以降低28.8%和31.6%的小鼠体重。而semaglutide只能降低16.0%的小鼠体重。以上结果表明SEQ ID NO:2和SEQ ID NO:7具有优异的减重作用,显著优于semaglutide。
表4:DIO小鼠治疗3周后的血清总胆固醇(TC)和甘油三酯(TG)含量
样品(剂量) | 总胆固醇(mmol/L) | 甘油三酯(mmol/L) |
空白对照(生理盐水组) | 9.15±0.56 | 1.98±0.22 |
Semaglutide(30nmol/kg) | 7.98±0.42** | 1.51±0.09* |
SEQ ID NO:2(30nmol/kg) | 3.68±0.55***,### | 0.63±0.18***,### |
SEQ ID NO:7(30nmol/kg) | 3.56±0.39***,### | 0.52±0.12***,### |
*:与空白对照组相比P<0.05;**:与空白对照组相比P<0.01;***:与空白对照组相比P<0.001;###:与semaglutide组比P<0.001(One-WayANOVA,Tukey post hoc test),结果表示为每组6只小鼠平均值±SD。
表5:DIO小鼠治疗3周后的肝脏总胆固醇(TC)和甘油三酯(TG)含量
样品(剂量) | 总胆固醇(mg/g) | 甘油三酯(mg/g) |
空白对照(生理盐水组) | 17.33±1.67 | 102.56±9.26 |
Semaglutide(30nmol/kg) | 14.33±1.22* | 85.33±7.25** |
SEQ ID NO:2(30nmol/kg) | 7.22±0.90***,### | 46.89±7.28***,### |
SEQ ID NO:7(30nmol/kg) | 7.05±0.41***,### | 42.25±5.33***,### |
*:与空白对照组相比P<0.05;**:与空白对照组相比P<0.01;***:与空白对照组相比P<0.001;###:与semaglutide组比P<0.001(One-WayANOVA,Tukey post hoc test),结果表示为每组6只小鼠平均值±SD。
如表4和表5结果显示,本发明的多肽化合物SEQ ID NO:2和SEQ ID NO:7在DIO小鼠体内连续给药3周,可以显著降低小鼠的血清和肝脏的甘油三酯(TG)和总胆固醇(TC)含量,并且SEQ ID NO:2和SEQ ID NO:7的降低血清和肝脏血脂的作用显著强于阳性对照药semaglutide。以上结果表明SEQ ID NO:2和SEQ ID NO:7具有显著优于semaglutide的减重和降低肝脏和血清血脂的效果,说明本发明的多肽化合物具有意想不到的异常优异的减重和调脂作用。
Claims (7)
1.一类GLP-1类似物,其特征在于,所述GLP-1类似物的氨基酸序列为下列序列之一:
(1)SEQ ID NO:1
(2)SEQ ID NO:2
(3)SEQ ID NO:3
(4)SEQ ID NO:4
(5)SEQ ID NO:5
(6)SEQ ID NO:6
(8)SEQ ID NO:8
(9)SEQ ID NO:9
(10)SEQ ID NO:10
。
2.一类GLP-1类似物药学上可接受的盐,其特征在于:所述的GLP-1类似物的氨基酸序列为权利要求1中所述的氨基酸序列之一。
3.根据权利要求2所述的一类GLP-1类似物药学上可接受的盐,其特在于,所述盐为GLP-1类似物与下述化合物中的一种所形成的盐:盐酸、乙酸、水杨酸、月桂酸、肉桂酸、柠檬酸草酸、乳酸、琥珀酸。
4.权利要求1所述的一类GLP-1类似物所制备的药剂,其特征在于,所述药剂是任何一种药剂学上所述的片剂、胶囊、吸入剂、喷雾剂、注射剂、膜剂、贴剂、乳剂或者复方制剂,药剂由一类GLP-1类似物和药学上可接受的药用辅料、载体或稀释剂组成。
5.含有一类GLP-1类似物的药物组合物,其特征在于,该药物组合物以权利要求1所述的GLP-1类似物为有效原料,或者以权利要求2或3所述的GLP-1类似物药学上可接受的盐为有效原料,再加上药学上可接受的载体或稀释剂组成。
6.权利要求1-5项中任意一项所述GLP-1类似物或其药学上可接受的盐、或其药物组合物或其药剂在制备用于治疗代谢性疾病或病症的药物中的用途。
7.根据权利要求6所述的用途,其特征在于,所述代谢性疾病或病症为糖尿病、肥胖症和血脂障碍。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310681999.XA CN116514952B (zh) | 2022-10-13 | 2022-10-13 | 一类glp-1类似物及其应用 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211252991.3A CN115785249B (zh) | 2022-10-13 | 2022-10-13 | 一类glp-1类似物及其应用 |
CN202310681999.XA CN116514952B (zh) | 2022-10-13 | 2022-10-13 | 一类glp-1类似物及其应用 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211252991.3A Division CN115785249B (zh) | 2022-10-13 | 2022-10-13 | 一类glp-1类似物及其应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN116514952A true CN116514952A (zh) | 2023-08-01 |
CN116514952B CN116514952B (zh) | 2024-02-02 |
Family
ID=85432893
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211252991.3A Active CN115785249B (zh) | 2022-10-13 | 2022-10-13 | 一类glp-1类似物及其应用 |
CN202310681999.XA Active CN116514952B (zh) | 2022-10-13 | 2022-10-13 | 一类glp-1类似物及其应用 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211252991.3A Active CN115785249B (zh) | 2022-10-13 | 2022-10-13 | 一类glp-1类似物及其应用 |
Country Status (1)
Country | Link |
---|---|
CN (2) | CN115785249B (zh) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101041693A (zh) * | 2007-02-06 | 2007-09-26 | 珠海联邦制药股份有限公司 | 一种新型降血糖多肽及其应用 |
CN102421797A (zh) * | 2009-07-30 | 2012-04-18 | 江苏豪森医药集团有限公司 | Glp-1类似物的衍生物或其可药用盐和用途 |
CN104327182A (zh) * | 2009-12-16 | 2015-02-04 | 诺沃—诺迪斯克有限公司 | 双酰化glp-1衍生物 |
CN110684082A (zh) * | 2019-10-08 | 2020-01-14 | 江苏诺泰澳赛诺生物制药股份有限公司 | Gip和glp-1双激动多肽化合物及药学上可接受的盐与用途 |
CN111253475A (zh) * | 2020-02-18 | 2020-06-09 | 江苏诺泰澳赛诺生物制药股份有限公司 | Glp-1激动多肽化合物及其盐与合成方法及用途 |
CN112236444A (zh) * | 2018-04-05 | 2021-01-15 | 太阳药业有限公司 | 新型glp-1类似物 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114349828B (zh) * | 2020-11-27 | 2023-12-08 | 江苏师范大学 | Glp-1/胰高血糖素受体双重激动剂及其应用 |
-
2022
- 2022-10-13 CN CN202211252991.3A patent/CN115785249B/zh active Active
- 2022-10-13 CN CN202310681999.XA patent/CN116514952B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101041693A (zh) * | 2007-02-06 | 2007-09-26 | 珠海联邦制药股份有限公司 | 一种新型降血糖多肽及其应用 |
CN102421797A (zh) * | 2009-07-30 | 2012-04-18 | 江苏豪森医药集团有限公司 | Glp-1类似物的衍生物或其可药用盐和用途 |
CN104327182A (zh) * | 2009-12-16 | 2015-02-04 | 诺沃—诺迪斯克有限公司 | 双酰化glp-1衍生物 |
CN112236444A (zh) * | 2018-04-05 | 2021-01-15 | 太阳药业有限公司 | 新型glp-1类似物 |
CN110684082A (zh) * | 2019-10-08 | 2020-01-14 | 江苏诺泰澳赛诺生物制药股份有限公司 | Gip和glp-1双激动多肽化合物及药学上可接受的盐与用途 |
CN111253475A (zh) * | 2020-02-18 | 2020-06-09 | 江苏诺泰澳赛诺生物制药股份有限公司 | Glp-1激动多肽化合物及其盐与合成方法及用途 |
Also Published As
Publication number | Publication date |
---|---|
CN115785249B (zh) | 2023-07-21 |
CN115785249A (zh) | 2023-03-14 |
CN116514952B (zh) | 2024-02-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR102351313B1 (ko) | Gip/glp1 공효능제 화합물 | |
CN112409460B (zh) | 一类glp-1/胰高血糖素受体双重激动剂及其应用 | |
CN111253475B (zh) | Glp-1激动多肽化合物及其盐与合成方法及用途 | |
CN116143884B (zh) | 一类长效GLP-1/glucagon/GIP受体三重激动剂及其应用 | |
WO2020103729A1 (zh) | 胰高血糖素衍生肽及其用途 | |
CN112724240A (zh) | 一类非洲爪蟾胰高血糖素样肽-1类似物及其应用 | |
WO2023000240A1 (zh) | 长效glp-1多肽类似物及其制备方法和应用 | |
US20230174608A1 (en) | Polypeptide Derivative Having Dual Receptor Agonistic Action and Use Thereof | |
CN110759991B (zh) | 吉非罗齐-非洲爪蟾胰高血糖素样肽-1衍生物及其应用 | |
CN116120425A (zh) | 一种glp-1/gip受体双重激动剂及其应用 | |
CN112608378B (zh) | 一类glp-1/胆囊收缩素-1受体双重激动剂及其应用 | |
WO2015149627A1 (zh) | 结构修饰的glp-1类似物及其制备方法 | |
CN115785249B (zh) | 一类glp-1类似物及其应用 | |
CN112759640B (zh) | 一类glp-1/胃泌素受体双重激动剂及其应用 | |
CN115960258B (zh) | 一类GLP-1/glucagon/Y2受体三重激动剂及其应用 | |
CN116589536B (zh) | 一类长效glp-1/gip受体双重激动剂及其应用 | |
CN115232200B (zh) | 长效化Exendin-4类似物及其应用 | |
CN117624333A (zh) | 一类GLP-1受体、glucagon受体和GIP受体三激动多肽化合物及其应用 | |
CN117417431A (zh) | 一类对glp-1、胰高血糖素和gip受体具有激动活性的多肽及其应用 | |
CN117417430A (zh) | 一类对glp-1和胰高血糖素受体具有激动活性的牛蛙glp-1类似物及其应用 | |
CN115819619A (zh) | 一类glp-1/y2受体双重激动剂及其应用 | |
CN115873096A (zh) | 一种胰高血糖素糖肽-1和胰高血糖素受体双重激动多肽及其应用 | |
CN117186189A (zh) | 一种兼具降糖和减重作用的glp-1/cck-1受体双重激动多肽及其应用 | |
KR20230106481A (ko) | 지속형 지방산-펩타이드 유도체 및 이의 용도 | |
CN115819551A (zh) | 一种定点改造的一类glp-1/胰高血糖素/胃泌素受体三重激动剂及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |