Design and synthesis of oxime ethers of α-acyl-β-phenylpropanoic acids as PPAR dual agonists

• Published in: Bioorganic & medicinal chemistry letters 2007-02, Vol.17 (4), p.937-941
• Main Authors: Oon Han, Hee, Hae Kim, Seung, Kim, Kyoung-Hee, Hur, Gwong-Cheung, Joo Yim, Hyeon, Chung, Hee-Kyung, Ho Woo, Sung, Dong Koo, Ki, Lee, Chang-Seok, Sung Koh, Jong, Tae Kim, Geun
• Format: Article
• Language: English
• Subjects: Animals; Area Under Curve; Biological and medical sciences; Biological Availability; Blood Glucose - metabolism; Cell Line, Tumor; Drug Design; Dual agonist; General and cellular metabolism. Vitamins; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; Indicators and Reagents; Lipids - blood; Magnetic Resonance Spectroscopy; Mass Spectrometry; Medical sciences; Mice; Models, Molecular; Oxime; Pharmacology. Drug treatments; Phenylpropionates - chemical synthesis; Phenylpropionates - pharmacology; PPAR; PPAR alpha - agonists; PPAR gamma - agonists; Propanoic acid; Structure-Activity Relationship; Thiazolidinediones - pharmacology; Triglycerides - blood
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.11.050

Compound 11l exhibited potent in vitro activities in PPARα and γ (EC 50 = 19, 13 nM). It showed better glucose lowering effect than rosiglitazone as well. Oxime ethers of α-acyl-β-phenylpropanoic acids were prepared to apply as PPARα and γ dual agonists. Among them, compound 11l proved to exhibit potent in vitro activities with EC 50 of 19 and 13 nM in PPARα and γ, respectively. It showed better glucose lowering effects than rosiglitazone 1 and ameliorated the lipid profile like plasma triglyceride in db/ db mice model.