title: Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modification.
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.
authors.affiliation: Zydus Research Centre, Sarkhej-Bavla N.H 8A Moraiya, Ahmedabad 382 210, India.
authors.forename: Pandurang
authors.initials: P
authors.lastname: Zaware
authors.forename: Shailesh R
authors.initials: SR
authors.lastname: Shah
authors.forename: Harikishore
authors.initials: H
authors.lastname: Pingali
authors.forename: Pankaj
authors.initials: P
authors.lastname: Makadia
authors.forename: Baban
authors.initials: B
authors.lastname: Thube
authors.forename: Suresh
authors.initials: S
authors.lastname: Pola
authors.forename: Darshit
authors.initials: D
authors.lastname: Patel
authors.forename: Priyanka
authors.initials: P
authors.lastname: Priyadarshini
authors.forename: Dinesh
authors.initials: D
authors.lastname: Suthar
authors.forename: Maanan
authors.initials: M
authors.lastname: Shah
authors.forename: Jeevankumar
authors.initials: J
authors.lastname: Jamili
authors.forename: Kalapatapu V V M
authors.initials: KV
authors.lastname: Sairam
authors.forename: Suresh
authors.initials: S
authors.lastname: Giri
authors.forename: Lala
authors.initials: L
authors.lastname: Patel
authors.forename: Harilal
authors.initials: H
authors.lastname: Patel
authors.forename: Hareshkumar
authors.initials: H
authors.lastname: Sudani
authors.forename: Hiren
authors.initials: H
authors.lastname: Patel
authors.forename: Mukul
authors.initials: M
authors.lastname: Jain
authors.forename: Pankaj
authors.initials: P
authors.lastname: Patel
authors.forename: Rajesh
authors.initials: R
authors.lastname: Bahekar
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004146:Dioxanes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010091:Oximes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D004146:Dioxanes; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D010091:Oximes; D047493:PPAR alpha; D047495:PPAR gamma