CN116115598A - 一种异黄酮醇化合物在制备预防或治疗代谢综合征药物中的用途 - Google Patents
一种异黄酮醇化合物在制备预防或治疗代谢综合征药物中的用途 Download PDFInfo
- Publication number
- CN116115598A CN116115598A CN202111349440.4A CN202111349440A CN116115598A CN 116115598 A CN116115598 A CN 116115598A CN 202111349440 A CN202111349440 A CN 202111349440A CN 116115598 A CN116115598 A CN 116115598A
- Authority
- CN
- China
- Prior art keywords
- compound
- medicament
- metabolic syndrome
- diabetic
- diabetes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 45
- 208000001145 Metabolic Syndrome Diseases 0.000 title claims abstract description 23
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims description 16
- -1 isoflavone alcohol compound Chemical class 0.000 title abstract description 9
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 title abstract description 4
- 235000008696 isoflavones Nutrition 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- 230000000694 effects Effects 0.000 claims abstract description 41
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 17
- 102000004136 Vasopressin Receptors Human genes 0.000 claims abstract description 15
- 108090000643 Vasopressin Receptors Proteins 0.000 claims abstract description 15
- 230000001991 pathophysiological effect Effects 0.000 claims abstract description 8
- 239000000018 receptor agonist Substances 0.000 claims abstract description 6
- 229940044601 receptor agonist Drugs 0.000 claims abstract description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims description 23
- 208000008589 Obesity Diseases 0.000 claims description 19
- 235000020824 obesity Nutrition 0.000 claims description 19
- 229940079593 drug Drugs 0.000 claims description 17
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 15
- 208000004930 Fatty Liver Diseases 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 206010019708 Hepatic steatosis Diseases 0.000 claims description 11
- 208000010706 fatty liver disease Diseases 0.000 claims description 11
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 9
- 208000030159 metabolic disease Diseases 0.000 claims description 8
- 206010020772 Hypertension Diseases 0.000 claims description 7
- 102000004169 proteins and genes Human genes 0.000 claims description 7
- 108090000623 proteins and genes Proteins 0.000 claims description 7
- 208000002249 Diabetes Complications Diseases 0.000 claims description 6
- 206010012655 Diabetic complications Diseases 0.000 claims description 6
- 230000001575 pathological effect Effects 0.000 claims description 6
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 5
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 5
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 claims description 5
- 102000002852 Vasopressins Human genes 0.000 claims description 5
- 108010004977 Vasopressins Proteins 0.000 claims description 5
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 claims description 5
- 210000004556 brain Anatomy 0.000 claims description 5
- 229960003726 vasopressin Drugs 0.000 claims description 5
- 210000002216 heart Anatomy 0.000 claims description 4
- 210000003734 kidney Anatomy 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 3
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 206010010356 Congenital anomaly Diseases 0.000 claims description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 2
- 208000010837 Diabetic eye disease Diseases 0.000 claims description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 2
- 208000021642 Muscular disease Diseases 0.000 claims description 2
- 201000009623 Myopathy Diseases 0.000 claims description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 2
- 150000001720 carbohydrates Chemical class 0.000 claims description 2
- 235000014633 carbohydrates Nutrition 0.000 claims description 2
- 238000013270 controlled release Methods 0.000 claims description 2
- 230000006735 deficit Effects 0.000 claims description 2
- 230000035487 diastolic blood pressure Effects 0.000 claims description 2
- 238000012377 drug delivery Methods 0.000 claims description 2
- 230000004064 dysfunction Effects 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000003228 microsomal effect Effects 0.000 claims description 2
- 230000003836 peripheral circulation Effects 0.000 claims description 2
- 238000013268 sustained release Methods 0.000 claims description 2
- 239000012730 sustained-release form Substances 0.000 claims description 2
- 230000035488 systolic blood pressure Effects 0.000 claims description 2
- 231100000216 vascular lesion Toxicity 0.000 claims description 2
- 239000003925 fat Substances 0.000 claims 1
- 210000005229 liver cell Anatomy 0.000 abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 11
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 11
- 201000010099 disease Diseases 0.000 abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 7
- 230000009467 reduction Effects 0.000 abstract description 6
- 230000004060 metabolic process Effects 0.000 abstract description 4
- 238000009825 accumulation Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 abstract description 2
- 229930186217 Glycolipid Natural products 0.000 abstract description 2
- 230000001105 regulatory effect Effects 0.000 abstract description 2
- GOMNOOKGLZYEJT-UHFFFAOYSA-N isoflavone Chemical compound C=1OC2=CC=CC=C2C(=O)C=1C1=CC=CC=C1 GOMNOOKGLZYEJT-UHFFFAOYSA-N 0.000 abstract 1
- 230000001737 promoting effect Effects 0.000 abstract 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 22
- 102000005962 receptors Human genes 0.000 description 16
- 108020003175 receptors Proteins 0.000 description 16
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 239000002609 medium Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 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 8
- 230000004913 activation Effects 0.000 description 8
- 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 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000008103 glucose Substances 0.000 description 8
- 229960001031 glucose Drugs 0.000 description 8
- 230000027455 binding Effects 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 238000003032 molecular docking Methods 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000035495 ADMET Effects 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 5
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 5
- 101150056450 UTS2R gene Proteins 0.000 description 5
- 238000010535 acyclic diene metathesis reaction Methods 0.000 description 5
- 230000008484 agonism Effects 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 229920001184 polypeptide Polymers 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- 208000024172 Cardiovascular disease Diseases 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 230000003833 cell viability Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- WYJCYXOCHXWTHG-UHFFFAOYSA-N 1-[2-(4-benzyl-4-hydroxypiperidin-1-yl)ethyl]-3-(2-methylquinolin-4-yl)urea Chemical compound C=12C=CC=CC2=NC(C)=CC=1NC(=O)NCCN(CC1)CCC1(O)CC1=CC=CC=C1 WYJCYXOCHXWTHG-UHFFFAOYSA-N 0.000 description 3
- 108010017384 Blood Proteins Proteins 0.000 description 3
- 102000004506 Blood Proteins Human genes 0.000 description 3
- 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 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 206010019851 Hepatotoxicity Diseases 0.000 description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 230000004190 glucose uptake Effects 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- 231100000304 hepatotoxicity Toxicity 0.000 description 3
- 230000007686 hepatotoxicity Effects 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 229960001855 mannitol Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 229950004355 palosuran Drugs 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000007901 soft capsule Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- 239000012224 working solution Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 240000006248 Broussonetia kazinoki Species 0.000 description 2
- 235000006716 Broussonetia kazinoki Nutrition 0.000 description 2
- 241000705930 Broussonetia papyrifera Species 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 101150050349 FFAR2 gene Proteins 0.000 description 2
- 101150108864 Ffar1 gene Proteins 0.000 description 2
- 101150008543 Ffar3 gene Proteins 0.000 description 2
- 102100040133 Free fatty acid receptor 2 Human genes 0.000 description 2
- 101000841325 Homo sapiens Urotensin-2 Proteins 0.000 description 2
- 101000644251 Homo sapiens Urotensin-2 receptor Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 102100020942 Urotensin-2 receptor Human genes 0.000 description 2
- 101100264077 Xenopus laevis wrn gene Proteins 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 230000007910 cell fusion Effects 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 208000016097 disease of metabolism Diseases 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000002662 enteric coated tablet Substances 0.000 description 2
- HVQAJTFOCKOKIN-UHFFFAOYSA-N flavonol Natural products O1C2=CC=CC=C2C(=O)C(O)=C1C1=CC=CC=C1 HVQAJTFOCKOKIN-UHFFFAOYSA-N 0.000 description 2
- 235000011957 flavonols Nutrition 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 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 2
- 230000003993 interaction Effects 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000004963 pathophysiological condition Effects 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000008299 semisolid dosage form Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000012096 transfection reagent Substances 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 208000004611 Abdominal Obesity Diseases 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 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
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- 206010065941 Central obesity Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 244000298479 Cichorium intybus Species 0.000 description 1
- 235000007542 Cichorium intybus Nutrition 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 231100000491 EC50 Toxicity 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 208000011514 Familial renal glucosuria Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000269828 Gillichthys mirabilis Species 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 229940122199 Insulin secretagogue Drugs 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
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 229940127470 Lipase Inhibitors Drugs 0.000 description 1
- 208000004852 Lung Injury Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000218231 Moraceae Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 229940122985 Peptide agonist Drugs 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 244000111146 Sonchus arvensis Species 0.000 description 1
- 235000006731 Sonchus arvensis Nutrition 0.000 description 1
- 208000006011 Stroke Diseases 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
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010069363 Traumatic lung injury Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000003579 anti-obesity Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229940095672 calcium sulfate Drugs 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 235000019577 caloric intake Nutrition 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000469 ethanolic extract Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 150000002216 flavonol derivatives Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229940124600 folk medicine Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003629 gastrointestinal hormone Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel 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
- 230000005182 global health Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000002064 heart cell Anatomy 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000004155 insulin signaling pathway Effects 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 231100000515 lung injury Toxicity 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 230000003880 negative regulation of appetite Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000607 neurosecretory system Anatomy 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000135 prohibitive effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000018598 regulation of vasoconstriction Effects 0.000 description 1
- 208000007278 renal glycosuria Diseases 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 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 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Gastroenterology & Hepatology (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及生物医疗领域,公开了一种异黄酮醇化合物在制备预防或治疗代谢综合征药物中的用途,具体公开了一种异黄酮醇类尾在制备具有尾加压素受体激动剂活性的药物中的应用,在制备预防或治疗以尾加压素II或尾加压素样肽低表达或活性降低为特征的病理生理或心理疾病药物中的应用,在制备治疗和/或预防代谢综合征药物中的应用。本发明的化合物可特异性激活尾加压素受体,具有显著促进降低肝细胞甘油三酯含量及减少肝细胞脂肪堆积,调节糖脂代谢的作用。该化合物作用新颖,容易合成,用量较低,具有很好的应用和开发前景。
Description
技术领域
本发明涉及生物医药领域,具体涉及一类新的具有尾加压素受体(urotensin-2receptor,UT)激动剂活性的化合物用于预防或治疗以尾加压素II或尾加压素样肽低表达或活性降低为特征的病理生理疾病的用途。尤其是在制备治疗和/或预防代谢综合征/2型糖尿病/肥胖/糖尿病/脂肪肝并发症药物中的应用。
背景技术
尾加压素II(U-II)是首先从虾虎鱼(Gillichthys mirabilis)的神经分泌系统中分离出来的多肽类物质,而后在人类中也克隆出了该多肽。U-II是高活性的内源性尾加压素受体(UT受体)肽激动剂。UT受体是一种G蛋白偶联受体,可通过Gαq信号转导。U-II等肽类是具有环状结构,含长度为11-15个氨基酸的多肽。人U-II(hU-II)为11个氨基酸的多肽。UT受体,也称为GPR14,参与血管收缩的调节。在哺乳动物中,U-II前体(UTS2)和UT受体基因(UTS2R)的mRNA广泛表达于中枢神经系统和周围组织,包括脑、肾、肝、肺、胰腺、骨骼肌和其他组织以及血管和心脏细胞。与广泛分布的U-II和UT受体相一致,尾加压素能系统与许多病理状态有关,包括动脉粥样硬化、心力衰竭、高血压、肾病和糖尿病。
随着对U-II系统机制研究的深入,以其为靶点的药物研发也是研究的重点,并有药物进入临床实验。目前UTR的激动剂及拮抗剂均有发现,研究较多的为拮抗剂,根据其物质特征可以分为多肽类和非肽类。其中palosuran是研究最为深入和广泛的UTR抑制剂,其在2003年以糖尿病肾病为适应症进入临床试验,但最终由于药效学不理想在2007年终止于Ⅱ期临床试验。有文献报道,palosuran可以改善糖尿病病人的肾病、心血管类疾病、肺损伤等。另有研究表明,U-II与胰岛素分泌减少、胰岛素信号通路损伤有关,但palosuran并未表现出逆转这一现象的作用,具体机制和原因还需要进一步探究。总体来说,以UTR为靶点的药物研究目前大多处于停滞状态,大多为疗效不明显的原因。我们研究发现,U-II本身可改善糖脂代谢,从另一方面解释了其拮抗剂的效果不良的原因,也说明尾加压素受体激动剂在对脂肪调节和糖耐量调节方面发挥重要作用。拓宽抗肥胖和2型糖尿病的选择领域因此开发新型具有尾加压素受体激动作用的药物至关重要。
代谢综合征是一组复杂的代谢紊乱症候群,是多种代谢成分异常聚集的病理状态,是导致糖尿病心脑血管疾病的危险因素。其具有以下特点:①多种代谢紊乱集于一身,包括肥胖、高血糖、高血压、血脂异常,这些代谢紊乱是心、脑血管病变以及糖尿病的病理基础;②有共同的病理基础,目前多认为它们的共同原因就是肥胖尤其是中心性肥胖所造成的胰岛素抵抗和高胰岛素血症;③可造成多种疾病累加,如高血压、冠心病、脑卒中、甚至某些癌症等。
肥胖是由体内过剩的能量在脂肪组织中过度堆积所引发的慢性代谢性疾病,是影响心脑血管疾病、糖尿病和肿瘤等的重大风险因素。限制能量摄入如节食、服用减肥药;或增加能量消耗如锻炼等策略因依从性差或药物副作用令肥胖症患者体重反弹,从而对减肥望而却步。因此,如何预防和治疗肥胖这一全球性健康问题,寻找安全有效的治疗方法成为国内外医学、营养学家致力研究的热点问题。
2型糖尿病是全球性流行的代谢性疾病,是心血管疾病的首要危险因素。在全球范围内,大约有3亿糖尿病患者,患者人数居高不下且仍不断上升,近年表现更甚。尤其在我国,随着我国人民生活水平的提高,饮食结构、生活习惯、环境条件等发生了巨大变化,与遗传、营养、代谢及环境等因素密切相关的糖代谢紊乱疾病的患病率急剧增加,且发展趋势尚未得到有效控制。由代谢性疾病引起的心脏、肾脏、脑和眼血管、神经等并发症不仅严重影响患者的生活质量,同时带来沉重的家庭和社会医疗负担。因此,2型糖尿病防治是我国目前面临的重大科学问题,探索防治糖代谢性疾病的有效措施,具有重要的科学价值和意义。
目前在临床上,治疗肥胖的药物主要包括食欲抑制剂:中枢抑制食欲药物,调节食欲的胃肠激素。作用于外周脂肪合成与分解的:作用在胃肠道减少脂肪吸收(脂肪酶抑制剂和钠-葡萄糖共转运体2抑制剂)。作用在脂肪组织减少脂肪合成、促进释放分解。2型糖尿病治疗的药物主要包括:胰岛素及其类似物、磺酰脲类、双胍类、α-葡萄糖苷酶抑制剂、噻唑烷二酮衍生物、促胰岛素分泌剂、中成药等。目前仍没有可减少代谢综合征和并发症的减肥产品。
本发明所述的(4H-1-苯并吡喃-4-酮-8-(1,1-二甲基-2-脯氨酸-1-烯)-3,5,7-三羟基-2-6-(8-羟基-2,2-二甲基-2H-1-苯并吡喃))(化合物11799),分子式为C25H24O7,分子量为436.45,气压760托时的预测沸点为650.7℃。化合物11799是从桑科植物苦苣苔树叶的乙醇提取物中分离得到的一种黄酮醇类化合物。苦苣苔的枝叶在中国民间医学中常被用作利尿剂、补药和水肿抑制剂,但目前尚无关于化合物11799药理活性的研究。
本发明所述的化合物11799,是经过实验研究获得的新的发现。新的发明内容主要涉及制备药物和药物组合。为临床提供预防或治疗以尾加压素II或尾加压素样肽及其受体低表达或活性降低为特征的病理生理疾病的用途,尤其是在制备治疗和/或预防代谢综合征/2型糖尿病/肥胖/糖尿病/脂肪肝并发症药物中的应用。目前有关化合物11799在尾加压素II或尾加压素样肽及其受体低表达或活性降低为特征的病理生理疾病的用途,尤其是在制备治疗和/或预防代谢综合征/2型糖尿病/肥胖/糖尿病/脂肪肝并发症药物中的应用方面直接或间接的治疗作用尚没有报道。
发明内容
本发明要解决的技术问题是,提供一种具有尾加压素受体激动剂活性的化合物在制备治疗和/或预防代谢综合征/2型糖尿病/肥胖/糖尿病/脂肪肝并发症药物中的应用。
为解决本发明的技术问题,本发明提供如下技术方案:
(1)本发明提供了如式(I)所示的化合物(即,化合物11799)在制备具有尾加压素受体激动剂活性的药物中的应用。
(2)本发明提供了如式(I)所示的化合物在制备预防或治疗以尾加压素II或尾加压素样肽低表达或活性降低为特征的病理生理或心理疾病药物中的应用。
(3)本发明提供了如式(I)所示的化合物在制备治疗和/或预防代谢综合征药物中的应用。其中,所述的代谢综合征包括肥胖、糖尿病、糖尿病并发症、脂肪肝、血脂异常、高血压。所述的代谢综合征包括各种原因导致的人体的蛋白质、脂肪、碳水化合物发生代谢紊乱的病理状态。
所述的糖尿病包括1型及2型糖尿病;所述的肥胖包括先天性、后天性、药物性原因导致的肥胖;所述的糖尿病并发症是指糖尿病大、小血管病变;所述的脂肪肝包括各种原因导致的肝脂肪变性;所述的血脂异常包括高甘油三酯、低高密度脂蛋白血症、高胆固醇血症;所述的高血压包括收缩压和或舒张压升高,可伴或不伴有心、脑、肾器官的功能或器质性损害。
进一步的,所述的糖尿病并发症包括糖尿病肾病、糖尿病末梢循环功能障碍、糖尿病外周神经病变、糖尿病眼病、糖尿病肌病、糖尿病合并高脂血症。
(4)本发明提供了一种药物组合物在在制备具有尾加压素受体激动剂活性的药物中的应用,在制备预防或治疗以尾加压素II或尾加压素样肽低表达或活性降低为特征的病理生理或心理疾病药物中的应用,制备治疗和/或预防代谢综合征药物中的应用,其特征在于,所述的药物组合物含有有效剂量的如式(I)所示的化合物及药用赋形剂;所述的药物组合物包括控制释放、持续释放制剂及微粒体给药系统的形式。
该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95%(重量)。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。一般来讲,本发明化合物的每天的合适剂量范围为0.001-150mg/kg体重,优选为0.1-100mg/kg体重,更优选为1-60mg/kg体重,最优选为2-30mg/kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。为了将给药单元制成胶囊剂,可以将有效成分本发明化合物与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。为将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
有益技术效果
1.本发明化合物(I)可调节尾加压素受体活性。关于本发明化合物对尾加压素受体活性调节的用途是首次公开。
2.本发明化合物(I)可预防或治疗以尾加压素II或尾加压素样肽及其受体低表达或活性降低为特征的病理生理疾病的用途。关于本化合物对该用途方面的报道为首次公开。
3.本发明化合物(I)可制备治疗和/或预防代谢综合征/2型糖尿病/肥胖/糖尿病/脂肪肝并发症药物中的用途。关于本化合物在该方面的用途为首次公开,拓宽相关疾病的选择药物。
4.目前在国际上,关于尾加压素激动作用公开了在心血管调节方面的专利(美国专利,专利号4533654,专利日期1985年8月6日)。我们前期的研究首次报道尾加压素激动在改善代谢综合征、肥胖和2型糖尿病的作用(一种多肽在制备预防或治疗代谢综合征药物中的用途。申请号CN110038114A)。关于本发明中化合物(I)对尾加压素系统方面的影响国际及国内未见相关论文及专利发表。
3.本发明的化合物通过新型靶点,用于预防或治疗以尾加压素II或尾加压素样肽及其受体低表达或活性降低为特征的病理生理疾病的用途。制备治疗和/或预防代谢综合征/2型糖尿病/肥胖/糖尿病/脂肪肝并发症药物中的用途。本发明的特点是靶向尾加压素系统并达到治疗及预防的效果。药物安全可靠。作为药物进行开发,具有明显的优益。
附图说明
图1.本发明化合物11799与尾加压素受体蛋白模型的对接结果。
图2.本发明化合物11799的ADMET预测结果。
图3.本发明化合物11799可剂量依赖性激活尾加压素受体,其半数有效浓度为8.97*10-8M。
图4.本发明化合物11799对尾加压素受体的激活具有特异性,不激活其他GPCR受体。
图5.本发明化合物11799对HepG2肝细胞葡萄糖吸收的影响。
图6.本发明化合物11799对HepG2肝细胞的乳酸释放的影响。
图7.本发明化合物11799对HepG2肝细胞活力的影响。
具体实施方式
下面结合本发明进一步说明本发明化合物(I),在本实施例中又称为11799,在调节尾加压素受体活性,预防或治疗以尾加压素II或尾加压素样肽及其受体低表达或活性降低为特征的病理生理疾病的用途。制备治疗和/或预防代谢综合征/2型糖尿病/肥胖/糖尿病/脂肪肝并发症药物中的用途。
下述实施例更详细地举例说明本发明,并不是对本发明的任何限制。所以熟悉本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整,仍属于本发明的保护范围。
实施例1.化合物11799的溶解及使用
化合物11799提取自小构树,即楮(学名:Broussonetia kazinoki)的干燥叶,具体提取方法见文献(Zhang PC,Wang S,Wu Y,Chen RY,Yu DQ.Five new diprenylatedflavonols from the leaves of Broussonetia kazinoki.J Nat Prod.2001 Sep;64(9):1206-9.doi:10.1021/np010283o.PMID:11575957.)。将化合物粉末溶解于DMSO中,配置成10mM的溶液,分装后,贮存于-80℃备用。使用时用生理盐水稀释至相应的浓度。
实施例2.化合物11799与尾加压素受体蛋白模型的对接
实验方法:在Discovery Studio中导入尾加压素受体蛋白结构的pdb文件和化合物11799的sdf文件,采用Discovery Studio中CDOCKER柔性对接方法进行蛋白-配体对接。首先,“Prepare Ligands”和“Prepare Protein”对化合物和蛋白进行处理,定义蛋白为受体分子,并预测受体结构的活性位点;运用“Receptor-Ligand Interactions”中的CDOCKER模块进行蛋白与化合物11799对接的操作,并设定相应参数。待程序运行结束后输出对接结果,对对接结果进行分析。
实验结果:分子对接是一种研究分子间(如配体和受体)相互作用,并预测其结合模式和亲合力的理论模拟方法,一般认为配体与受体结合的构象稳定时能量越低,发生的作用可能性越大。化合物11799与受体蛋白的结合能为-12.32kcal/mol,提示化合物11799与受体的结合活性较高。化合物11799与受体生成的配体-蛋白相互作用二维平面图见图1,化合物11799与氨基酸残基Arg81形成氢键作用,与氨基酸残基PYR87形成Pi-Pi作用,增加了分子与蛋白的作用。结果见图1。
实施例3.化合物11799的成药性评价
实验方法:用Discovery Studio软件中的ADMET模块,将化合物11799的sdf文件导入DS软件中,在“Small Molecules”模块中选定“Calculate Molecular Properties”点击ADMET descriptors进行参数设置,点击运行,对化合物的吸收、分布、代谢、排泄和毒性进行预测,获得化合物11799的被动肠内吸收性、25℃的水溶性、血脑屏障穿透性、人细胞色素CYP4502D6酶结合、肝毒性、血浆蛋白结合等方面的数据。
实验结果:ADMET预测结果见图2。化合物11799相对应的水溶性值logSW为-5.17,CYP4502D6酶的抑制数为2.14e-07,在0水平范围内,无抑制作用。化合物11799的肝毒性测定值为0.022,无肝毒性。化合物11799与血浆蛋白结合值为4.13,提示我们血浆中可能大部分药物仍为游离型,仅少部分与血浆蛋白结合。结果见表1和图2。
表1化合物11799的ADMET预测结果
实施例4.化合物11799对尾加压素受体的激活作用
实验方法:HEK293细胞培养于含10%灭活胎牛血清的4.5g/L DMEM高糖培养液中,置于37℃、5%CO2细胞培养箱中。当细胞密度达到80%时,以1:3的比例传代培养。当细胞融合度达到70%时,弃去原培养基,换用8ml DMEM继续培养4h。4h后,从培养基中吸出4mlDMEM并补加4ml含10%胎牛血清的DMEM培养基。以每皿DMEM:UTR:PEI=800μl:10μg:40μl的比例配制转染液,转染试剂用量按照质粒浓度不同需要进行调整。将转染液混合均匀,静置15-20min后滴入细胞。细胞转染24h后,弃去原培养基,4mL生理盐水清洗两次,加入1mL胰酶后置于培养箱中消化1-2min,将细胞转入离心管中,800r离心3min,弃去上清,加入10%胎牛血清的DMEM培养基,反复吹打细胞至细胞混匀,以1.5*105/孔接种至96孔板中,于37℃、5%CO2培养箱中培养24h。细胞种板24h后,将化合物11799储备液用生理盐水进行梯度稀释,使终浓度分别为10-10M、10-9M、10-8M、10-7M、10-6M、10-5M,加入不同浓度的化合物1179910μl/孔。细胞给药24h后,弃去培养液上清,加入Bright-Glo试剂50μl/孔,使用M5酶标仪检测化学发光强度。
实验结果:HEK293细胞给予不同浓度的化合物11799刺激后,在10-10M~10-5M范围内,化合物11799的激动作用呈现良好的浓度依赖关系,即随化合物11799的浓度升高,激动作用越强,经计算得化合物11799的半数有效浓度为8.97*10-8M。结果见表2和图3。
表2化合物11799对尾加压素受体的激活作用
实施例5.化合物11799对其他GPCR受体的激活作用
实验方法:HEK293细胞培养于含10%灭活胎牛血清的4.5g/L DMEM高糖培养液中,置于37℃、5%CO2细胞培养箱中。当细胞密度达到80%时,以1:3的比例传代培养。当细胞融合度达到70%时,弃去原培养基,换用8ml DMEM继续培养4h。4h后,从培养基中吸出4mlDMEM并补加4ml含10%胎牛血清的DMEM培养基。分别转染GPCR质粒FFA1,FFA2,FFA3,以每皿DMEM:质粒:PEI=800μl:10μg:40μl的比例配制转染液,转染试剂用量按照质粒浓度不同需要进行调整。将转染液混合均匀,静置15-20min后滴入细胞。余下操作同实施例4。
实验结果:HEK293细胞给予不同浓度的化合物11799刺激后,只有转染UTS2R质粒的HEK293细胞的激活作用呈现出浓度依赖关系,而转染FFA1,FFA2,FFA3质粒的HEK293细胞则无明显的激活作用。提示化合物11799对尾加压素受体的激活具有特异性,而不激活其他GPCR受体。结果见表3和图4。
表3化合物11799对尾加压素受体的特异性激活作用
实施例6.化合物11799对HepG2肝细胞葡萄糖吸收的影响
实验方法:HepG2肝细胞培养于含10%灭活胎牛血清的4.5g/L DMEM高糖培养液中,置于37℃、5%CO2细胞培养箱中。当细胞密度达到90%时,用胰蛋白酶消化,以1:3的比例传代培养。取对数生长期的细胞以100μl/孔(1*105个/ml)接种于96孔板中培养24h,24h后,弃去原培养基,加入含10%胎牛血清的无酚红的1640培养基100μl/孔。同时将化合物11799储备液用生理盐水进行梯度稀释,使终浓度分别为10-9M、10-8M、10-7M、10-6M、10-5M,加入不同浓度的化合物1179910μl/孔。继续培养48h后,每孔吸出10μl培养基上清加到新的96孔中,另加10μl标准对照品和10μl纯水;加入葡萄糖测试工作液R1100μl/孔,混匀后置于37℃保温4min,于340nm处读取吸光度值;再加入葡萄糖测试工作液R225μl/孔,混匀后置于37℃保温5min,于340nm处读取吸光度值。
实验结果:化合物11799作用48h后,与对照组相比,在10-9M-10-5M浓度时均可显著性促进HepG2肝细胞葡萄糖吸收。其中以10-5M作用最为显著。结果见表4和图5。
表4化合物11799对HepG2肝细胞葡萄糖吸收的影响
实施例7.化合物11799对HepG2肝细胞乳酸释放的影响
实验方法:细胞培养,种板,给药的操作见实施例6。乳酸含量检测方法如下:细胞培养48h后,每孔吸出10μl培养基上清,稀释10倍后,取20μl加到新的96孔中,另加20μl标准对照品和20μl纯水;加入酶工作液50μl/孔,显色液10μl/孔,混匀后置于37℃气浴中准确反应10min;再加入终止液100μl/孔,充分混匀后于530nm处读取吸光度值。
实验结果:化合物11799作用48h后,与对照组相比,在10-9M-10-5M浓度时均可显著性减少HepG2肝细胞的乳酸释放。结果见表5和图6。
表5化合物11799对HepG2肝细胞乳酸释放的影响
实施例8.化合物11799对HepG2肝细胞活力的影响
实验方法:细胞培养,种板,给药的操作见实施例6。细胞活力检测方法如下:细胞培养24h后,弃去原培养基,在96孔板中加入CCK8稀释液100μl/孔,并置于37℃培养箱中孵育约30min,于450nm处读取吸光度值。
实验结果:化合物11799作用24h后,与对照组相比,在10-9M-10-5M浓度时对HepG2肝细胞活力无显著性影响。结果见表6和图7。
表6化合物11799对HepG2肝细胞活力的影响
Claims (9)
4.根据权利要求3的应用,其特征在于,所述的代谢综合征包括肥胖、糖尿病、糖尿病并发症、脂肪肝、血脂异常、高血压。
5.根据权利要求3的应用,其特征在于,所述的代谢综合征包括各种原因导致的人体的蛋白质、脂肪、碳水化合物发生代谢紊乱的病理状态。
6.根据权利要求4的应用,其特征在于,所述的糖尿病包括1型及2型糖尿病;所述的肥胖包括先天性、后天性、药物性原因导致的肥胖;所述的糖尿病并发症是指糖尿病大、小血管病变;所述的脂肪肝包括各种原因导致的肝脂肪变性;所述的血脂异常包括高甘油三酯、低高密度脂蛋白血症、高胆固醇血症;所述的高血压包括收缩压和或舒张压升高,可伴或不伴有心、脑、肾器官的功能或器质性损害。
7.根据权利要求4的应用,其特征在于,所述的糖尿病并发症包括糖尿病肾病、糖尿病末梢循环功能障碍、糖尿病外周神经病变、糖尿病眼病、糖尿病肌病、糖尿病合并高脂血症。
9.根据权利要求8的应用,其特征在于,所述的药物组合物包括控制释放、持续释放制剂及微粒体给药系统的形式。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111349440.4A CN116115598A (zh) | 2021-11-15 | 2021-11-15 | 一种异黄酮醇化合物在制备预防或治疗代谢综合征药物中的用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111349440.4A CN116115598A (zh) | 2021-11-15 | 2021-11-15 | 一种异黄酮醇化合物在制备预防或治疗代谢综合征药物中的用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116115598A true CN116115598A (zh) | 2023-05-16 |
Family
ID=86293699
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111349440.4A Pending CN116115598A (zh) | 2021-11-15 | 2021-11-15 | 一种异黄酮醇化合物在制备预防或治疗代谢综合征药物中的用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116115598A (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101269061A (zh) * | 2007-03-20 | 2008-09-24 | 华中科技大学 | 甲氧基黄酮类化合物作为防治代谢综合征的药物及用法 |
US20100291248A1 (en) * | 2009-05-12 | 2010-11-18 | Korea Research Institute Of Bioscience And Biotechnology | Compositions for Preventing and Treating Obesity, Hyperlipidemia, Atherosclerosis, Fatty Liver, Diabetes or Metabolic Syndrome Containing Extracts of Glycine Max Leaves or Fractions Isolated from the Same as an Active Ingredient |
CN102188489A (zh) * | 2010-03-04 | 2011-09-21 | 天阳制纸(株) | 含有楮树提取物而可以增强免疫功能的组成物 |
KR20160001935A (ko) * | 2014-06-30 | 2016-01-07 | 원광대학교산학협력단 | 블랙 커런트 추출물을 유효성분으로 함유하는 대사증후군의 예방, 개선 또는 치료를 위한 조성물 |
US20190075823A1 (en) * | 2015-08-19 | 2019-03-14 | Korea Research Institute Of Bioscience And Biotechnology | Composition for prevention or treatment of metabolic syndrome or for antioxidation containing black bean leaf extracts and flavonol glysosides isolated therefrom as active ingredients |
-
2021
- 2021-11-15 CN CN202111349440.4A patent/CN116115598A/zh active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101269061A (zh) * | 2007-03-20 | 2008-09-24 | 华中科技大学 | 甲氧基黄酮类化合物作为防治代谢综合征的药物及用法 |
US20100291248A1 (en) * | 2009-05-12 | 2010-11-18 | Korea Research Institute Of Bioscience And Biotechnology | Compositions for Preventing and Treating Obesity, Hyperlipidemia, Atherosclerosis, Fatty Liver, Diabetes or Metabolic Syndrome Containing Extracts of Glycine Max Leaves or Fractions Isolated from the Same as an Active Ingredient |
CN102188489A (zh) * | 2010-03-04 | 2011-09-21 | 天阳制纸(株) | 含有楮树提取物而可以增强免疫功能的组成物 |
KR20160001935A (ko) * | 2014-06-30 | 2016-01-07 | 원광대학교산학협력단 | 블랙 커런트 추출물을 유효성분으로 함유하는 대사증후군의 예방, 개선 또는 치료를 위한 조성물 |
US20190075823A1 (en) * | 2015-08-19 | 2019-03-14 | Korea Research Institute Of Bioscience And Biotechnology | Composition for prevention or treatment of metabolic syndrome or for antioxidation containing black bean leaf extracts and flavonol glysosides isolated therefrom as active ingredients |
Non-Patent Citations (3)
Title |
---|
PEI CHENG ZHANG等: "A New Isoprenylated flavonol from the Leaves of Broussonetia kazinoki", CHINESE CHEMICAL LETTERS, vol. 12, no. 2, pages 141 - 142 * |
PEI-CHENG ZHANG等: "Five New Diprenylated Flavonols from the Leaves of Broussonetia kazinoki", J. NAT. PROD., vol. 64, pages 1206 - 1209 * |
马养民;吉艳芬;: "构树属植物活性成分的提取分离研究进展", 中药材, vol. 31, no. 01, pages 161 - 164 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104981240B (zh) | 通过控制血糖水平用于治疗糖尿病及相关病症的组合物、方法以及用途 | |
CN107441078B (zh) | 一种治疗糖尿病的药物组合物及其制备方法和用途 | |
TW200808324A (en) | Method for shortening hospital stay in patients with congestive heart failure and acute fluid overload | |
KR20110117257A (ko) | 트리에틸아세틸기-3-히드록실기페닐기아데노신 및 혈지조절에 대한 용도 | |
CN110420315A (zh) | 枸杞糖肽在制备治疗三高药物中的应用 | |
CN116531368A (zh) | 一种glp-1r激动剂 | |
CN104350051B (zh) | 用于糖尿病的异噁唑治疗剂 | |
CN104557944B (zh) | 一种降糖药物及其制备方法 | |
CN104892529A (zh) | 一种含喹唑啉结构的硫脲类化合物及其制备方法和应用 | |
EA004250B1 (ru) | Терапевтический агент для диабета | |
CN116115598A (zh) | 一种异黄酮醇化合物在制备预防或治疗代谢综合征药物中的用途 | |
JP2006515276A (ja) | 骨粗鬆症の予防及び治療効果を有するフラン誘導体並びにこれを含む薬学的組成物 | |
CN116098904A (zh) | 一种酰基哌嗪类化合物在制备预防或治疗代谢综合征药物中的用途 | |
CN116139127A (zh) | 一种酰胺类化合物在制备预防或治疗代谢综合征药物中的用途 | |
CN109200273B (zh) | 一种多肽用于制备预防或治疗脂肪肝病药物的用途 | |
CN1814616A (zh) | 黄杨碱、黄杨碱盐酸盐及其制备方法和制成的制剂 | |
KR100732614B1 (ko) | 복어 추출물을 포함하는 비만 또는 당뇨성 질환의 예방또는 치료용 약학 조성물 | |
CN113209099A (zh) | 木兰花碱在制备调节食欲亢进或治疗肥胖症的药物中的应用 | |
CN104873482B (zh) | 一种抗慢性心力衰竭的药物组合物 | |
CN110934864A (zh) | 4-甲基-6,7-二甲氧基香豆素在制备防治糖尿病肾病的药物中的应用 | |
CN111606909B (zh) | 吡唑并嘧啶类化合物及其药物组合物及制备方法和应用 | |
CN103058976B (zh) | 槲皮素α晶型物质、其制法和其药物组合物与用途 | |
CN110256461A (zh) | 稠杂嘧啶衍生物及其制备方法和应用 | |
CN112190570B (zh) | 天麻来源衍生物在制备治疗急性或慢性疼痛药物中的用途 | |
CN111195247B (zh) | 一种α-葡萄糖苷酶抑制剂及其在降血糖药物中的应用 |
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 |