Synthesis and structure-activity relationships of 2-aryl-4-oxazolylmethoxy benzylglycines and 2-aryl-4-thiazolylmethoxy benzylglycines as novel, potent PPARalpha selective activators- PPARalpha and PPARgamma selectivity modulation

• Published in: Bioorganic & medicinal chemistry letters 2010-05, Vol.20 (9), p.2933-2937
• Main Authors: Ye, Xiang-Yang, Chen, Stephanie, Zhang, Hao, Locke, Kenneth T, O'Malley, Kevin, Zhang, Litao, Srivastava, Raijit, Miao, Bowman, Meyers, Daniel, Monshizadegan, Hossain, Search, Debra, Grimm, Denise, Zhang, Rongan, Lippy, Jonathan, Twamley, Celeste, Muckelbauer, Jodi K, Chang, Chiehying, An, Yongmi, Hosagrahara, Vinayak, Zhang, Lisa, Yang, T-J, Mukherjee, Ranjan, Cheng, Peter T W, Tino, Joseph A
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacokinetics; Binding Sites; Cricetinae; Crystallography, X-Ray; Glycine - analogs & derivatives; Glycine - chemical synthesis; Glycine - pharmacokinetics; Humans; Male; PPAR alpha - agonists; PPAR alpha - metabolism; PPAR gamma - agonists; PPAR gamma - metabolism; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship
• ISSN: 1464-3405
• DOI: 10.1016/j.bmcl.2010.03.019

The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARalpha/gamma dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARalpha versus PPARgamma. Potent, highly selective PPARalpha activators 2a and 2l, as well as PPARalpha activators with significant PPARgamma activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed.