Novel 2,3-dihydrobenzofuran-2-carboxylic acids: highly potent and subtype-selective PPARalpha agonists with potent hypolipidemic activity.
The design and synthesis of a novel class of 2,3-dihydrobenzofuran-2-carboxylic acids as highly potent and subtype-selective PPARalpha agonists are reported. Systematic study of structure-activity relationships has identified several key structural elements within this class for maintaining the potency and subtype selectivity. Select compounds were evaluated in animal models of dyslipidemia using Syrian hamsters and male Beagle dogs, and all these compounds displayed excellent cholesterol- and triglyceride-lowering activity at dose levels that were much lower than the marketed weak PPARalpha agonist fenofibrate.
Shi
Guo Q
GQ
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065-0900, USA. guoqiang_shi@merck.com
Dropinski
James F
JF
Zhang
Yong
Y
Santini
Conrad
C
Sahoo
Soumya P
SP
Berger
Joel P
JP
Macnaul
Karen L
KL
Zhou
Gaochao
G
Agrawal
Arun
A
Alvaro
Raul
R
Cai
Tian-Quan
TQ
Hernandez
Melba
M
Wright
Samuel D
SD
Moller
David E
DE
Heck
James V
JV
Meinke
Peter T
PT
D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D006224:Cricetinae; D004285:Dogs; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008647:Mesocricetus; D008968:Molecular Conformation; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics; D011869:Radioligand Assay; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D014280:Triglycerides / Q000097:blood
C504523:2-ethyl-5-(3-(2-chloro-4-(trifluoromethoxy)phenoxy)propoxy)-2,3-dihydro-1-benzofuran-2-carboxylic acid; D001572:Benzofurans; D002264:Carboxylic Acids; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D014280:Triglycerides; D002784:Cholesterol