title: Design and synthesis of novel oxazole containing 1,3-dioxane-2-carboxylic acid derivatives as PPAR alpha/gamma dual agonists.
abstract: A few novel 1,3-dioxane carboxylic acid derivatives were designed and synthesized to aid in the characterization of PPAR alpha/gamma dual agonists. Structural requirements for PPARalpha/gamma dual agonism of 1,3-dioxane carboxylic acid derivatives included the structural similarity with potent glitazones in fibric acid chemotype. The compounds with this pharmacophore and substituted oxazole as a lipophilic heterocyclic tail were synthesized and evaluated for their in vitro PPAR agonistic potential and in vivo hypoglycemic and hypolipidemic efficacy in animal models. Lead compound 2-methyl-c-5-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-ylmethoxy)-benzyl]-1,3-dioxane-r-2-carboxylic acid 13b exhibited potent hypoglycemic, hypolipidemic and insulin sensitizing effects in db/db mice and Zucker fa/fa rats.
authors.affiliation: Zydus Research Centre, Sarkhej-Bavla N.H 8A Moraiya, Ahmedabad 382210, India. pingalihk@rediffmail.com
authors.forename: Harikishore
authors.initials: H
authors.lastname: Pingali
authors.forename: Mukul
authors.initials: M
authors.lastname: Jain
authors.forename: Shailesh
authors.initials: S
authors.lastname: Shah
authors.forename: Pankaj
authors.initials: P
authors.lastname: Makadia
authors.forename: Pandurang
authors.initials: P
authors.lastname: Zaware
authors.forename: Ashish
authors.initials: A
authors.lastname: Goel
authors.forename: Megha
authors.initials: M
authors.lastname: Patel
authors.forename: Suresh
authors.initials: S
authors.lastname: Giri
authors.forename: Harilal
authors.initials: H
authors.lastname: Patel
authors.forename: Pankaj
authors.initials: P
authors.lastname: Patel
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology*; D003920:Diabetes Mellitus / Q000188:drug therapy; D015195:Drug Design; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry* / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D011924:Rats, Zucker; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D007004:Hypoglycemic Agents; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma