Design and synthesis of novel oxazole containing 1,3-dioxane-2-carboxylic acid derivatives as PPAR alpha/gamma dual agonists.

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Pingali H, Jain M, Shah S, Makadia P, Zaware P, Goel A, Patel M, Giri S, Patel H, Patel P

Design and synthesis of novel oxazole containing 1,3-dioxane-2-carboxylic acid derivatives as PPAR alpha/gamma dual agonists.

Bioorg Med Chem. 2008 Aug 1;16(15):7117-27. doi: 10.1016/j.bmc.2008.06.050. Epub 2008 Jun 28.

PubMed ID

18625559 [ View in PubMed

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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-diox ane-r-2-carboxylic acid 13b exhibited potent hypoglycemic, hypolipidemic and insulin sensitizing effects in db/db mice and Zucker fa/fa rats.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	50	N/A	N/A	Details