Studies on antidiabetic agents. 11. Novel thiazolidinedione derivatives as potent hypoglycemic and hypolipidemic agents.
In the course of further chemical modification of the novel antidiabetic pioglitazone (AD-4833, U-72,107), a series of 5-[4-(2- or 4-azolylalkoxy)benzyl- or -benzylidene]-2,4-thiazolidinediones was prepared and evaluated for hypoglycemic and hypolipidemic activities in insulin-resistant, genetically obese, and diabetic KKA(y) mice. Replacement of the 2-pyridyl moiety of pioglitazone by a 2- or 4-oxazolyl or a 2- or 4-thiazolyl moiety greatly enhanced in vivo potency. The corresponding 5-benzylidene-type compounds, in which a methine was used as a linker between the benzene ring and the thiazolidinedione ring, also had potent biological activity. Among the compounds synthesized, 5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-2,4- thiazolidinedione (18) exhibited the most potent activity, more than 100 times that of pioglitazone. The synthesis and structure-activity relationships for this novel series of derivatives are detailed.
Sohda
T
T
Research and Development Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Mizuno
K
K
Momose
Y
Y
Ikeda
H
H
Fujita
T
T
Meguro
K
K
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D007333:Insulin Resistance; D051379:Mice; D000077205:Pioglitazone; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D045162:Thiazolidinediones
D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D000077205:Pioglitazone