(2R)-2-methylchromane-2-carboxylic acids: discovery of selective PPARalpha agonists as hypolipidemic agents.
A SAR study was conducted on chromane-2-carboxylic acid toward selective PPARalpha agonisim. As a result, highly potent, and selective PPARalpha agonists were discovered. The optimized compound 43 exhibited robust lowering of total cholesterol levels in hamster and dog animal models.
Koyama
Hiroo
H
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000 Rahway, NJ 07065, USA. hiroo_koyama@merck.com
Boueres
Julia K
JK
Miller
Daniel J
DJ
Berger
Joel P
JP
MacNaul
Karen L
KL
Wang
Pei-ran
PR
Ippolito
Marc C
MC
Wright
Samuel D
SD
Agrawal
Arun K
AK
Moller
David E
DE
Sahoo
Soumya P
SP
D000818:Animals; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D002839:Chromans / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D006224:Cricetinae; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D002839:Chromans; D000960:Hypolipidemic Agents; D047493:PPAR alpha