Studies on Non-Thiazolidinedione Antidiabetic Agents. 2. Novel Oxyiminoalkanoic Acid Derivatives as Potent Glucose and Lipid Lowering Agents

摘要

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)-γ. 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 PPARγ. In vivo potencies of synthesized compounds, which showed strong functional activity at PPARγ, 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 at-tractive candidate for further evaluation.