Design and synthesis of novel oxazole containing 1,3-Dioxane-2-carboxylic acid derivatives as PPAR α/γ dual agonists

A novel class of PPARα/γ dual agonists containing 1,3-dioxane-2-carboxylic acid was described. Compound 13b exhibited potent hypoglycemic, hypolipidemic and insulin sensitizing effects in db/ db mice and Zucker fa/ fa rats. A few novel 1,3-dioxane carboxylic acid derivatives were designed and synthe...

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Published in:Bioorganic & medicinal chemistry 2008-08, Vol.16 (15), p.7117-7127
Main Authors: Pingali, Harikishore, Jain, Mukul, Shah, Shailesh, Makadia, Pankaj, Zaware, Pandurang, Goel, Ashish, Patel, Megha, Giri, Suresh, Patel, Harilal, Patel, Pankaj
Format: Article
Language:English
Subjects:
1,3-Dioxane carboxylic acid
Animals
Biological and medical sciences
Carboxylic Acids - chemistry
Carboxylic Acids - pharmacology
Diabetes Mellitus - drug therapy
Drug Design
General and cellular metabolism. Vitamins
Hypoglycemic Agents - chemistry
Hypoglycemic Agents - pharmacology
Medical sciences
Mice
Mice, Inbred NOD
Molecular Structure
Oxazole
Oxazoles - chemistry
Oxazoles - pharmacology
Pharmacology. Drug treatments
PPAR agonist
PPAR alpha - agonists
PPAR gamma - agonists
Rats
Rats, Zucker
Structure-Activity Relationship
Type 2 diabetes
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Summary:A novel class of PPARα/γ dual agonists containing 1,3-dioxane-2-carboxylic acid was described. Compound 13b exhibited potent hypoglycemic, hypolipidemic and insulin sensitizing effects in db/ db mice and Zucker fa/ fa rats. A few novel 1,3-dioxane carboxylic acid derivatives were designed and synthesized to aid in the characterization of PPAR α/γ dual agonists. Structural requirements for PPARα/γ 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.06.050