Synthesis and SAR of selective benzothiophene, benzofuran, and indole-based peroxisome proliferator-activated receptor delta agonists.
Recent literature has suggested the benefit of selective PPARdelta agonists for the treatment of atherosclerosis and other disease states associated with the metabolic syndrome. Herein we report the synthesis and structure-activity relationships of a series of novel and selective PPARdelta agonists. Our search began with identification of a novel benzothiophene template which was modified by the addition of various thiazolyl, isoxazolyl, and benzyloxy-benzyl moieties. Further elucidation of the SAR led to the identification of benzofuran and indole based templates. During the course of our research, we discovered three new chemical templates with varying degrees of affinity and potency for PPARdelta versus the PPARalpha and PPARgamma subtypes.
Filzen
Gary F
GF
Department of Chemistry, Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI 48105, USA. Gary.filzen@pfizer.com <Gary.filzen@pfizer.com>
Bratton
Larry
L
Cheng
Xue-Min
XM
Erasga
Noe
N
Geyer
Andrew
A
Lee
Chitase
C
Lu
Gina
G
Pulaski
Jim
J
Sorenson
Roderick J
RJ
Unangst
Paul C
PC
Trivedi
B K
BK
Xu
Xiangyang
X
D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008024:Ligands; D008956:Models, Chemical; D047494:PPAR delta / Q000819:agonists*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry*
D001572:Benzofurans; D007211:Indoles; D008024:Ligands; D047494:PPAR delta; D013844:Thiazoles; D013876:Thiophenes; C105430:benzofuran