Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modification

Pandurang Zaware,Darshit Patel,Suresh Giri,Rajesh Bahekar,Baban Thube,Lala Patel,Maanan Shah,Kalapatapu V.V.M Sairam,Harilal Patel,Dinesh Suthar,Priyanka Priyadarshini,Harikishore Pingali,Suresh Pola,Jeevankumar Jamili,Hareshkumar Sudani,Panlcaj Makadia ,Hiren Patel ,Mukul Jain ,Pankaj Patel ,Shailesh R Shah

doi:10.1016/j.bmcl.2010.12.032

Pandurang Zaware, Darshit Patel + Show 18 more

https://doi.org/10.1016/j.bmcl.2010.12.032

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Abstract

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

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