Studies on non-thiazolidinedione antidiabetic agents. 2. Novel oxyiminoalkanoic acid derivatives as potent glucose and lipid lowering agents.
We previously reported that (Z)-2-(4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino)-2-(4-phenoxyphenyl)acetic acid (3) showed potent glucose and lipid lowering effects in genetically obese and diabetic mice, KKA(y). This compound also showed transcriptional activity for peroxisome proliferator-activated receptor (PPAR)-gamma. We expanded on the structure-activity relationships of oxyiminoalkanoic acid derivatives based on this transcriptional activity (in vitro). Insertion of a carbon chain between the imino carbon and the carboxyl moiety of (Z)-2-(4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino)-2-phenylacetic acid (2) resulted in a marked increase in transcriptional activity at PPARgamma. In vivo potencies of synthesized compounds, which showed strong functional activity at PPARgamma, were tested using KKA(y) mice. Among these compounds, (E)-4-(4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino)-4-phenylbutyric acid (27) exhibited marked glucose and lipid lowering activity while showing no significant body weight gain. Compound (27) (TAK-559) showed favorable pharmacokinetic properties with good absorption and duration, and was considered as an attractive candidate for further evaluation.
Imoto
Hiroshi
H
Takeda Chemical Industries, Ltd., Pharmaceutical Research Division, Osaka, Japan. Imoto_Hiroshi@takeda.co.jp
Sugiyama
Yasuo
Y
Kimura
Hiroyuki
H
Momose
Yu
Y
D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology*; D007098:Imino Acids / Q000737:chemistry / Q000494:pharmacology; D008055:Lipids / Q000037:antagonists & inhibitors* / Q000097:blood; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000302:isolation & purification; D045162:Thiazolidinediones
D000475:Alkenes; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007098:Imino Acids; D008055:Lipids; D013844:Thiazoles; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione