Modulation Of Ppar Subtype Selectivity. Part 2: Transforming Ppar Alpha/Gamma Dual Agonist Into Alpha Selective Ppar Agonist Through Bioisosteric Modification

A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPAR alpha agonists, through bioisosteric modification in the lipophilic tail region of PPAR alpha/gamma dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPAR alpha over PPAR gamma in vitro. Further, highly potent and selective PPAR alpha agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPAR alpha binding pocket correlate its in vitro selectivity profile toward PPAR alpha over PPAR gamma. Together, these results confirm discovery of novel series of oxime based selective PPAR alpha agonists for the safe and effective treatment of various metabolic disorders. (C) 2010 Elsevier Ltd. All rights reserved.