ZA200105016B - A combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes. - Google Patents
A combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes. Download PDFInfo
- Publication number
- ZA200105016B ZA200105016B ZA200105016A ZA200105016A ZA200105016B ZA 200105016 B ZA200105016 B ZA 200105016B ZA 200105016 A ZA200105016 A ZA 200105016A ZA 200105016 A ZA200105016 A ZA 200105016A ZA 200105016 B ZA200105016 B ZA 200105016B
- Authority
- ZA
- South Africa
- Prior art keywords
- group
- alkyl
- aryl
- composition
- alicyclic
- Prior art date
Links
- 229940122355 Insulin sensitizer Drugs 0.000 title claims description 146
- 101710099475 3'-phosphoadenosine 5'-phosphate phosphatase Proteins 0.000 title claims description 83
- 101710196411 Fructose-1,6-bisphosphatase Proteins 0.000 title claims description 83
- 101710186733 Fructose-1,6-bisphosphatase, chloroplastic Proteins 0.000 title claims description 83
- 101710109119 Fructose-1,6-bisphosphatase, cytosolic Proteins 0.000 title claims description 83
- 101710198902 Fructose-1,6-bisphosphate aldolase/phosphatase Proteins 0.000 title claims description 83
- 239000003112 inhibitor Substances 0.000 title claims description 77
- 206010012601 diabetes mellitus Diseases 0.000 title claims description 43
- 125000000217 alkyl group Chemical group 0.000 claims description 205
- 125000003118 aryl group Chemical group 0.000 claims description 172
- 125000002723 alicyclic group Chemical group 0.000 claims description 112
- 239000000203 mixture Substances 0.000 claims description 110
- 150000001875 compounds Chemical class 0.000 claims description 107
- 239000000126 substance Substances 0.000 claims description 98
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 94
- 238000000034 method Methods 0.000 claims description 93
- 229940002612 prodrug Drugs 0.000 claims description 85
- 239000000651 prodrug Substances 0.000 claims description 85
- -1 SB219993 Chemical compound 0.000 claims description 77
- 125000004122 cyclic group Chemical group 0.000 claims description 73
- 239000003795 chemical substances by application Substances 0.000 claims description 70
- 150000003839 salts Chemical class 0.000 claims description 69
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 54
- 125000005843 halogen group Chemical group 0.000 claims description 54
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 48
- 125000000304 alkynyl group Chemical group 0.000 claims description 39
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims description 37
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims description 37
- 125000004429 atom Chemical group 0.000 claims description 37
- 206010022489 Insulin Resistance Diseases 0.000 claims description 36
- 125000003342 alkenyl group Chemical group 0.000 claims description 36
- 201000010099 disease Diseases 0.000 claims description 36
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 36
- 239000003814 drug Substances 0.000 claims description 35
- 229940123464 Thiazolidinedione Drugs 0.000 claims description 33
- 239000003446 ligand Substances 0.000 claims description 33
- 125000005842 heteroatom Chemical group 0.000 claims description 32
- 239000000556 agonist Substances 0.000 claims description 29
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical group O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 claims description 28
- 229910052799 carbon Inorganic materials 0.000 claims description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 25
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- 229910052717 sulfur Inorganic materials 0.000 claims description 23
- 241001465754 Metazoa Species 0.000 claims description 22
- 239000008103 glucose Substances 0.000 claims description 22
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 21
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 20
- 229910052698 phosphorus Inorganic materials 0.000 claims description 20
- 238000002560 therapeutic procedure Methods 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 201000001421 hyperglycemia Diseases 0.000 claims description 15
- 125000004423 acyloxy group Chemical group 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 13
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 239000011574 phosphorus Substances 0.000 claims description 12
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 206010020772 Hypertension Diseases 0.000 claims description 11
- 150000001721 carbon Chemical group 0.000 claims description 11
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 10
- 125000001543 furan-2,5-diyl group Chemical group O1C(=CC=C1*)* 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 238000001727 in vivo Methods 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 230000002440 hepatic effect Effects 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- 230000001965 increasing effect Effects 0.000 claims description 8
- 125000004437 phosphorous atom Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- IRAAJHYKQDFNFO-SFHVURJKSA-N (2s)-3-[4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid Chemical compound N=1C2=CC=CC=C2OC=1N(C)CCOC1=CC=C(C[C@H](OCC(F)(F)F)C(O)=O)C=C1 IRAAJHYKQDFNFO-SFHVURJKSA-N 0.000 claims description 7
- 208000008589 Obesity Diseases 0.000 claims description 7
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 230000004110 gluconeogenesis Effects 0.000 claims description 7
- 210000003494 hepatocyte Anatomy 0.000 claims description 7
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 7
- 235000020824 obesity Nutrition 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims description 6
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 5
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 claims description 4
- 239000005541 ACE inhibitor Substances 0.000 claims description 4
- 206010036049 Polycystic ovaries Diseases 0.000 claims description 4
- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 4
- 229960001445 alitretinoin Drugs 0.000 claims description 4
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 4
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 4
- 125000005200 aryloxy carbonyloxy group Chemical group 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 4
- 238000000338 in vitro Methods 0.000 claims description 4
- 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 4
- 230000009229 glucose formation Effects 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000005205 alkoxycarbonyloxyalkyl group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000005750 substituted cyclic group Chemical group 0.000 claims description 2
- 150000007970 thio esters Chemical class 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 35
- 241000124008 Mammalia Species 0.000 claims 19
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims 18
- 238000004519 manufacturing process Methods 0.000 claims 18
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims 12
- 150000003462 sulfoxides Chemical class 0.000 claims 12
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims 9
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims 9
- 150000001409 amidines Chemical class 0.000 claims 9
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims 9
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims 9
- 201000001320 Atherosclerosis Diseases 0.000 claims 7
- 208000035150 Hypercholesterolemia Diseases 0.000 claims 7
- 208000031226 Hyperlipidaemia Diseases 0.000 claims 7
- 208000037906 ischaemic injury Diseases 0.000 claims 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 6
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims 6
- AFSHNJLKCYAWRX-UHFFFAOYSA-N 4-[(5-chloronaphthalen-2-yl)methyl]-5h-1,2,3,5-oxathiadiazole 2-oxide Chemical compound C=1C=C2C(Cl)=CC=CC2=CC=1CC1=NS(=O)ON1 AFSHNJLKCYAWRX-UHFFFAOYSA-N 0.000 claims 6
- MVDXXGIBARMXSA-PYUWXLGESA-N 5-[[(2r)-2-benzyl-3,4-dihydro-2h-chromen-6-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CC=C(O[C@@H](CC=2C=CC=CC=2)CC2)C2=C1 MVDXXGIBARMXSA-PYUWXLGESA-N 0.000 claims 6
- YVQKIDLSVHRBGZ-UHFFFAOYSA-N 5-[[4-[2-hydroxy-2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1C(O)COC(C=C1)=CC=C1CC1SC(=O)NC1=O YVQKIDLSVHRBGZ-UHFFFAOYSA-N 0.000 claims 6
- YZFWTZACSRHJQD-UHFFFAOYSA-N ciglitazone Chemical compound C=1C=C(CC2C(NC(=O)S2)=O)C=CC=1OCC1(C)CCCCC1 YZFWTZACSRHJQD-UHFFFAOYSA-N 0.000 claims 6
- 229950009226 ciglitazone Drugs 0.000 claims 6
- QQKNSPHAFATFNQ-UHFFFAOYSA-N darglitazone Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1CCC(=O)C(C=C1)=CC=C1CC1SC(=O)NC1=O QQKNSPHAFATFNQ-UHFFFAOYSA-N 0.000 claims 6
- 229950006689 darglitazone Drugs 0.000 claims 6
- 229950002375 englitazone Drugs 0.000 claims 6
- 229960005095 pioglitazone Drugs 0.000 claims 6
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 claims 6
- 229960001641 troglitazone Drugs 0.000 claims 6
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 claims 6
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 5
- 229910006069 SO3H Inorganic materials 0.000 claims 5
- 229910052711 selenium Inorganic materials 0.000 claims 5
- ZZCHHVUQYRMYLW-HKBQPEDESA-N farglitazar Chemical compound N([C@@H](CC1=CC=C(C=C1)OCCC=1N=C(OC=1C)C=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 ZZCHHVUQYRMYLW-HKBQPEDESA-N 0.000 claims 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 4
- 125000006366 methylene oxy carbonyl group Chemical group [H]C([H])([*:1])OC([*:2])=O 0.000 claims 4
- 229940123073 Angiotensin antagonist Drugs 0.000 claims 3
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 claims 3
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 claims 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims 3
- 125000005647 linker group Chemical group 0.000 claims 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 3
- 239000002461 renin inhibitor Substances 0.000 claims 3
- 229940086526 renin-inhibitors Drugs 0.000 claims 3
- 125000005415 substituted alkoxy group Chemical group 0.000 claims 3
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 claims 2
- LMWZLUIVVPBIQZ-UHFFFAOYSA-N 1-oxothiolan-2-one Chemical group O=C1CCCS1=O LMWZLUIVVPBIQZ-UHFFFAOYSA-N 0.000 claims 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 claims 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims 1
- 125000004530 1,2,4-triazinyl group Chemical group N1=NC(=NC=C1)* 0.000 claims 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims 1
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 claims 1
- 101000973200 Homo sapiens Nuclear factor 1 C-type Proteins 0.000 claims 1
- 102000034570 NR1 subfamily Human genes 0.000 claims 1
- 108020001305 NR1 subfamily Proteins 0.000 claims 1
- 102100022162 Nuclear factor 1 C-type Human genes 0.000 claims 1
- 101000973172 Sus scrofa Nuclear factor 1 Proteins 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 125000001786 isothiazolyl group Chemical group 0.000 claims 1
- 125000000842 isoxazolyl group Chemical group 0.000 claims 1
- 125000002757 morpholinyl group Chemical group 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000002971 oxazolyl group Chemical group 0.000 claims 1
- 125000003226 pyrazolyl group Chemical group 0.000 claims 1
- 125000002098 pyridazinyl group Chemical group 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- 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 48
- 125000002947 alkylene group Chemical group 0.000 description 38
- 102000004877 Insulin Human genes 0.000 description 23
- 108090001061 Insulin Proteins 0.000 description 23
- 229940125396 insulin Drugs 0.000 description 23
- 238000002648 combination therapy Methods 0.000 description 16
- 229940079593 drug Drugs 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 102000004190 Enzymes Human genes 0.000 description 13
- 108090000790 Enzymes Proteins 0.000 description 13
- 238000003556 assay Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 229940100389 Sulfonylurea Drugs 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 125000002877 alkyl aryl group Chemical group 0.000 description 8
- 238000010171 animal model Methods 0.000 description 8
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical group [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 8
- 150000001467 thiazolidinediones Chemical class 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000002641 glycemic effect Effects 0.000 description 7
- 230000009471 action Effects 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 230000007423 decrease Effects 0.000 description 6
- 230000003914 insulin secretion Effects 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 210000001789 adipocyte Anatomy 0.000 description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 5
- 230000010030 glucose lowering effect Effects 0.000 description 5
- 102000003923 Protein Kinase C Human genes 0.000 description 4
- 108090000315 Protein Kinase C Proteins 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 125000001769 aryl amino group Chemical group 0.000 description 4
- 125000004104 aryloxy group Chemical group 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 235000005911 diet Nutrition 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 230000002093 peripheral effect Effects 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- 108010017464 Fructose-Bisphosphatase Proteins 0.000 description 3
- 102000027487 Fructose-Bisphosphatase Human genes 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- 208000021017 Weight Gain Diseases 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 238000010719 annulation reaction Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000002837 carbocyclic group Chemical group 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 150000001923 cyclic compounds Chemical class 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 235000021588 free fatty acids Nutrition 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000003285 pharmacodynamic effect Effects 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- 102000008169 Co-Repressor Proteins Human genes 0.000 description 2
- 108010060434 Co-Repressor Proteins Proteins 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 2
- 108010044467 Isoenzymes Proteins 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 108090000854 Oxidoreductases Proteins 0.000 description 2
- 102000004316 Oxidoreductases Human genes 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- 125000005354 acylalkyl group Chemical group 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 2
- 125000005110 aryl thio group Chemical group 0.000 description 2
- 125000005841 biaryl group Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 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 2
- 230000001684 chronic effect Effects 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 239000002359 drug metabolite Substances 0.000 description 2
- 230000034659 glycolysis Effects 0.000 description 2
- 239000000833 heterodimer Substances 0.000 description 2
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 2
- 201000008980 hyperinsulinism Diseases 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000001294 propane Substances 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 150000007944 thiolates Chemical class 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000013293 zucker diabetic fatty rat Methods 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- VAYTZRYEBVHVLE-UHFFFAOYSA-N 1,3-dioxol-2-one Chemical class O=C1OC=CO1 VAYTZRYEBVHVLE-UHFFFAOYSA-N 0.000 description 1
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- KBSDLBVPAHQCRY-UHFFFAOYSA-N 307496-19-1 Chemical group C1CC=CCC1CC[Si](O1)(O2)O[Si](O3)(C4CCCC4)O[Si](O4)(C5CCCC5)O[Si]1(C1CCCC1)O[Si](O1)(C5CCCC5)O[Si]2(C2CCCC2)O[Si]3(C2CCCC2)O[Si]41C1CCCC1 KBSDLBVPAHQCRY-UHFFFAOYSA-N 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- VIWUAZHGPJCGFP-UHFFFAOYSA-N CC=1C(=C(C(=C2CCCC(C=12)C(=O)C1=C(C(=O)O)C=CC=C1)C)C)C Chemical class CC=1C(=C(C(=C2CCCC(C=12)C(=O)C1=C(C(=O)O)C=CC=C1)C)C)C VIWUAZHGPJCGFP-UHFFFAOYSA-N 0.000 description 1
- DEVWEFBXXYMHIL-UHFFFAOYSA-N CCCOP(O)=O Chemical compound CCCOP(O)=O DEVWEFBXXYMHIL-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 101100202237 Danio rerio rxrab gene Proteins 0.000 description 1
- 101100309320 Danio rerio rxrga gene Proteins 0.000 description 1
- 101100439669 Drosophila melanogaster chrb gene Proteins 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- YXWOAJXNVLXPMU-ZXXMMSQZSA-N Fructose 2,6-diphosphate Chemical class OP(=O)(O)O[C@]1(CO)O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O YXWOAJXNVLXPMU-ZXXMMSQZSA-N 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 108010086800 Glucose-6-Phosphatase Proteins 0.000 description 1
- 102000003638 Glucose-6-Phosphatase Human genes 0.000 description 1
- 101000741788 Homo sapiens Peroxisome proliferator-activated receptor alpha Proteins 0.000 description 1
- 101000640876 Homo sapiens Retinoic acid receptor RXR-beta Proteins 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 206010070070 Hypoinsulinaemia Diseases 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- 206010052341 Impaired insulin secretion Diseases 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 239000004158 L-cystine Substances 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
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 206010054805 Macroangiopathy Diseases 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 102100038831 Peroxisome proliferator-activated receptor alpha Human genes 0.000 description 1
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 1
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 108010053763 Pyruvate Carboxylase Proteins 0.000 description 1
- 102100039895 Pyruvate carboxylase, mitochondrial Human genes 0.000 description 1
- 101150050070 RXRA gene Proteins 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 102100034253 Retinoic acid receptor RXR-beta Human genes 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000007824 aliphatic compounds Chemical class 0.000 description 1
- 125000004171 alkoxy aryl group Chemical group 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000002058 anti-hyperglycaemic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 125000005518 carboxamido group Chemical group 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000012761 co-transfection Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 230000006377 glucose transport Effects 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 230000004121 glycogenesis Effects 0.000 description 1
- 230000002414 glycolytic effect Effects 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000035860 hypoinsulinemia Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000002608 insulinlike Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000009149 molecular binding Effects 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 229940127209 oral hypoglycaemic agent Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 229930029653 phosphoenolpyruvate Natural products 0.000 description 1
- DTBNBXWJWCWCIK-UHFFFAOYSA-K phosphonatoenolpyruvate Chemical compound [O-]C(=O)C(=C)OP([O-])([O-])=O DTBNBXWJWCWCIK-UHFFFAOYSA-K 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 description 1
- 150000008298 phosphoramidates Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- GPKJTRJOBQGKQK-UHFFFAOYSA-N quinacrine Chemical compound C1=C(OC)C=C2C(NC(C)CCCN(CC)CC)=C(C=CC(Cl)=C3)C3=NC2=C1 GPKJTRJOBQGKQK-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 108020003113 steroid hormone receptors Proteins 0.000 description 1
- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003239 susceptibility assay Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000012622 synthetic inhibitor Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004014 thioethyl group Chemical group [H]SC([H])([H])C([H])([H])* 0.000 description 1
- 108090000721 thyroid hormone receptors Proteins 0.000 description 1
- 102000004217 thyroid hormone receptors Human genes 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 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
- 210000002700 urine Anatomy 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- 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
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- 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
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11471898P | 1998-12-24 | 1998-12-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200105016B true ZA200105016B (en) | 2002-09-19 |
Family
ID=22357016
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200105016A ZA200105016B (en) | 1998-12-24 | 2001-06-19 | A combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes. |
Country Status (25)
| Country | Link |
|---|---|
| EP (1) | EP1143955B1 (fr) |
| JP (1) | JP2003515523A (fr) |
| KR (3) | KR20060114724A (fr) |
| CN (3) | CN1714866A (fr) |
| AT (1) | ATE300288T1 (fr) |
| AU (1) | AU771039B2 (fr) |
| BR (1) | BR9917005A (fr) |
| CA (1) | CA2354053A1 (fr) |
| CZ (1) | CZ20012353A3 (fr) |
| DE (1) | DE69926400T2 (fr) |
| DK (1) | DK1143955T3 (fr) |
| ES (1) | ES2246586T3 (fr) |
| HK (1) | HK1046863B (fr) |
| HU (1) | HUP0402506A3 (fr) |
| ID (1) | ID30237A (fr) |
| IL (2) | IL143569A0 (fr) |
| MX (1) | MXPA01006511A (fr) |
| NO (1) | NO20013115L (fr) |
| NZ (1) | NZ512219A (fr) |
| PL (1) | PL352756A1 (fr) |
| PT (1) | PT1143955E (fr) |
| RU (2) | RU2227749C2 (fr) |
| SK (1) | SK9172001A3 (fr) |
| WO (1) | WO2000038666A2 (fr) |
| ZA (1) | ZA200105016B (fr) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998039344A1 (fr) | 1997-03-07 | 1998-09-11 | Metabasis Therapeutics, Inc. | Nouveaux composes de purine inhibiteurs de fructose-1,6-biophasphatase |
| US6312662B1 (en) | 1998-03-06 | 2001-11-06 | Metabasis Therapeutics, Inc. | Prodrugs phosphorus-containing compounds |
| WO2000014095A1 (fr) | 1998-09-09 | 2000-03-16 | Metabasis Therapeutics, Inc. | Nouveaux inhibiteurs heteroaromatiques de fructose-1,6-biphosphatase |
| EP1240174A2 (fr) * | 1999-12-22 | 2002-09-18 | Metabasis Therapeutics, Inc. | Promedicaments a base de bisamidate phosphonate |
| DE60125734T2 (de) * | 2000-03-08 | 2007-10-25 | Metabasis Therapeutics, Inc., La Jolla | Neue aryl fructose-1,6-bisphosphatase inhibitoren |
| KR100854851B1 (ko) * | 2000-07-06 | 2008-08-27 | 메타베이시스 테라퓨틱스, 인크. | 당뇨병 치료에 유용한 ＦＢＰａｓｅ 억제제와 항당뇨제의조합물 |
| US7022725B2 (en) | 2000-11-17 | 2006-04-04 | Takeda Pharmaceutical Company Limited | Isoxazole derivatives |
| NZ536328A (en) | 2002-05-13 | 2007-11-30 | Metabasis Therapeutics Inc | Novel phosphonic acid based prodrugs of PMEA and its analogues |
| EP1504014B1 (fr) | 2002-05-13 | 2015-12-02 | Metabasis Therapeutics, Inc. | Procede d'elaboration de promedicaments cycliques de pmea et de pmpa |
| JP4719465B2 (ja) * | 2002-09-04 | 2011-07-06 | ディーエスエム アイピー アセッツ ビー．ブイ． | インスリン感受性増強剤およびペプチド画分を含む栄養補給用および治療用組成物 |
| UA80991C2 (en) | 2002-10-07 | 2007-11-26 | Solid preparation containing an insulin resistance improving drug and an active ingredient useful as a remedy for diabetes | |
| CA2515726C (fr) * | 2003-02-11 | 2012-07-10 | Vernalis (Cambridge) Limited | Isoxazoles |
| EP3002283B1 (fr) * | 2003-12-26 | 2017-06-14 | Kyowa Hakko Kirin Co., Ltd. | Dérivés de thiazole |
| WO2006023515A2 (fr) * | 2004-08-18 | 2006-03-02 | Metabasis Therapeutics, Inc. | Nouveaux inhibiteurs thiazole de la fructose 1,6-bisphosphatase |
| WO2006064744A1 (fr) * | 2004-12-13 | 2006-06-22 | Daiichi Sankyo Company, Limited | Composition medicinale pour le traitement du diabete |
| TW200633702A (en) * | 2004-12-15 | 2006-10-01 | Sankyo Co | Medicinal composition containing fbpase inhibitor |
| EP1889618A4 (fr) * | 2005-05-27 | 2010-11-24 | Daiichi Sankyo Co Ltd | Médicament combiné pour le traitement du diabète |
| US20100280023A1 (en) | 2005-06-23 | 2010-11-04 | Kyowa Hakko Kogyo Co., Ltd. | Thiazole derivatives |
| EP2089017A2 (fr) | 2006-11-02 | 2009-08-19 | Aestus Therapeutics, Inc. | Procédés de traitement de la douleur neuropathique par la modulation des voies de la glycogénolyse ou de la glycolyse |
| CN107312039B (zh) | 2012-08-30 | 2019-06-25 | 江苏豪森药业集团有限公司 | 一种替诺福韦前药的制备方法 |
| US9631825B2 (en) | 2012-12-18 | 2017-04-25 | Nortek Air Solutions, Llc | Air filter assembly |
| JP2017512183A (ja) | 2014-02-13 | 2017-05-18 | リガンド・ファーマシューティカルズ・インコーポレイテッド | プロドラッグ化合物およびそれらの使用 |
| CN106687118A (zh) | 2014-07-02 | 2017-05-17 | 配体药物公司 | 前药化合物及其用途 |
| CN105481896A (zh) * | 2015-12-03 | 2016-04-13 | 浙江大学 | 一种地马格列的制备方法 |
| CN113416739B (zh) * | 2021-06-24 | 2022-04-19 | 黑龙江八一农垦大学 | 鲁氏酵母菌基因在提高微生物产hdmf的产量中的应用 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4968790A (en) * | 1988-08-12 | 1990-11-06 | American Cyanamid Company | Antidiabetic phosphates |
| JPH03157377A (ja) * | 1988-11-18 | 1991-07-05 | Takeda Chem Ind Ltd | チオ尿素誘導体及びａｇｅ生成阻害剤 |
| CA2008325A1 (fr) * | 1989-01-24 | 1990-07-24 | Harry E. Gruber | Methode et compose pour la liberation de ribosides et l'abaissement de la glycemie |
| TWI238064B (en) * | 1995-06-20 | 2005-08-21 | Takeda Chemical Industries Ltd | A pharmaceutical composition for prophylaxis and treatment of diabetes |
| US5859037A (en) * | 1997-02-19 | 1999-01-12 | Warner-Lambert Company | Sulfonylurea-glitazone combinations for diabetes |
| WO1998039344A1 (fr) * | 1997-03-07 | 1998-09-11 | Metabasis Therapeutics, Inc. | Nouveaux composes de purine inhibiteurs de fructose-1,6-biophasphatase |
| AU6691498A (en) * | 1997-03-07 | 1998-09-22 | Metabasis Therapeutics, Inc. | Novel benzimidazole inhibitors of fructose-1,6-bisphosphatase |
| AU6691798A (en) * | 1997-03-07 | 1998-09-22 | Metabasis Therapeutics, Inc. | Novel indole and azaindole inhibitors of fructose-1,6-bisphosphatase |
-
1999
- 1999-12-22 PL PL99352756A patent/PL352756A1/xx not_active Application Discontinuation
- 1999-12-22 ES ES99964313T patent/ES2246586T3/es not_active Expired - Lifetime
- 1999-12-22 DK DK99964313T patent/DK1143955T3/da active
- 1999-12-22 CN CNA2005100806150A patent/CN1714866A/zh active Pending
- 1999-12-22 BR BR9917005-1A patent/BR9917005A/pt not_active Application Discontinuation
- 1999-12-22 ID IDW00200101612A patent/ID30237A/id unknown
- 1999-12-22 CN CNB998163562A patent/CN100352505C/zh not_active Expired - Fee Related
- 1999-12-22 KR KR1020067022095A patent/KR20060114724A/ko not_active Application Discontinuation
- 1999-12-22 CN CNA2007101628889A patent/CN101164618A/zh active Pending
- 1999-12-22 KR KR1020017008102A patent/KR100689943B1/ko not_active IP Right Cessation
- 1999-12-22 HU HU0402506A patent/HUP0402506A3/hu active IP Right Revival
- 1999-12-22 CZ CZ20012353A patent/CZ20012353A3/cs unknown
- 1999-12-22 CA CA002354053A patent/CA2354053A1/fr not_active Abandoned
- 1999-12-22 PT PT99964313T patent/PT1143955E/pt unknown
- 1999-12-22 JP JP2000590620A patent/JP2003515523A/ja active Pending
- 1999-12-22 AT AT99964313T patent/ATE300288T1/de active
- 1999-12-22 NZ NZ512219A patent/NZ512219A/xx not_active IP Right Cessation
- 1999-12-22 SK SK917-2001A patent/SK9172001A3/sk unknown
- 1999-12-22 EP EP99964313A patent/EP1143955B1/fr not_active Expired - Lifetime
- 1999-12-22 KR KR1020077008649A patent/KR20070046210A/ko not_active Application Discontinuation
- 1999-12-22 IL IL14356999A patent/IL143569A0/xx active IP Right Grant
- 1999-12-22 MX MXPA01006511A patent/MXPA01006511A/es active IP Right Grant
- 1999-12-22 WO PCT/US1999/030713 patent/WO2000038666A2/fr active Application Filing
- 1999-12-22 DE DE69926400T patent/DE69926400T2/de not_active Expired - Lifetime
- 1999-12-22 AU AU20583/00A patent/AU771039B2/en not_active Ceased
- 1999-12-22 RU RU2001120726/15A patent/RU2227749C2/ru not_active IP Right Cessation
-
2001
- 2001-06-05 IL IL143569A patent/IL143569A/en not_active IP Right Cessation
- 2001-06-19 ZA ZA200105016A patent/ZA200105016B/en unknown
- 2001-06-21 NO NO20013115A patent/NO20013115L/no not_active Application Discontinuation
-
2002
- 2002-11-22 HK HK02108475.5A patent/HK1046863B/zh not_active IP Right Cessation
-
2003
- 2003-10-31 RU RU2003132054/14A patent/RU2003132054A/ru not_active Application Discontinuation
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ZA200105016B (en) | A combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes. | |
| ZA200207004B (en) | Novel aryl fructose-1,6-bisphosphatase inhibitors. | |
| US5084479A (en) | Novel methods for treating neurodegenerative diseases | |
| Arima et al. | Glomerular prostaglandins modulate vascular reactivity of the downstream efferent arterioles | |
| CA2727064C (fr) | Combinaison de pilocarpine et de methimazol destinee au traitement de la maladie de charcot-marie-tooth et de troubles associes | |
| EP2380566A2 (fr) | Traitement de la résistance d'insuline ou maladies associées à la résistance d'insuline utilisant Stéviol ou Isosteviol | |
| Ramakrishnan et al. | HIF2α is an essential molecular brake for postprandial hepatic glucagon response independent of insulin signaling | |
| JP2008545696A (ja) | 肥満の処置のためのｐ３８ｍａｒｋの阻害 | |
| RU2328308C2 (ru) | Комбинирование ингибиторов fbp-азы и антидиабетических средств для лечения диабета | |
| Callsen et al. | Nitric oxide and superoxide inhibit platelet-derived growth factor receptor phosphotyrosine phosphatases | |
| NL8802634A (nl) | Therapeutische preparaten. | |
| US8410085B2 (en) | Phospholipid compositions and uses thereof | |
| CA2332272A1 (fr) | Nouveaux analogues d'acide 16-hydroxyeicosatetraenoique | |
| KR20100096077A (ko) | 에포틸론 또는 에포틸론 유도체 유발성 설사의 치료를 위한 코르티코스테로이드 | |
| Assael et al. | Prostaglandins and aminoglycoside nephrotoxicity | |
| Gauthier et al. | Influence of a GABAB receptor antagonist on the sleep–waking cycle in the rat | |
| Okada et al. | Protein kinase associated with gating and closing transmission mechanisms in temporoammonic pathway | |
| AU2017252126B2 (en) | Use of thyroid beta-agonists | |
| JP2008081427A (ja) | 分泌障害性疾患の予防及び／又は治療のための医薬 | |
| CA2514090C (fr) | Utilisation de composes stimulant la synthese du glutathion dans la reduction de la resistance a l'insuline | |
| KR20050090443A (ko) | 랑게르한스섬 세포 수를 증가시킴으로써 당뇨병을 치료하는키뉴레닌-３-하이드록실라제 저해제 | |
| AU2017252122A1 (en) | Use of Thyroid beta-Agonists | |
| AU2003201579A1 (en) | Use of glutathione synthesis stimulating compounds in reducing insulin resistance | |
| Ribeiro et al. | Methylmalonate-induced seizures are attenuated in inducible nitric oxide synthase knockout mice | |
| ZA200101711B (en) | Novel heteroaromatic inhibitors of fructose 1,6-bisphosphatase. |