Design and synthesis of novel oxazole containing 1,3-dioxane-2-carboxylic acid derivatives as PPAR alpha/gamma dual agonists.
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.
Pingali
Harikishore
H
Zydus Research Centre, Sarkhej-Bavla N.H 8A Moraiya, Ahmedabad 382210, India. pingalihk@rediffmail.com
Jain
Mukul
M
Shah
Shailesh
S
Makadia
Pankaj
P
Zaware
Pandurang
P
Goel
Ashish
A
Patel
Megha
M
Giri
Suresh
S
Patel
Harilal
H
Patel
Pankaj
P
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
D002264:Carboxylic Acids; D007004:Hypoglycemic Agents; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma