title: Novel 2,3-dihydrobenzofuran-2-carboxylic acids: highly potent and subtype-selective PPARalpha agonists with potent hypolipidemic activity.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065-0900, USA. guoqiang_shi@merck.com
authors.forename: Guo Q
authors.initials: GQ
authors.lastname: Shi
authors.forename: James F
authors.initials: JF
authors.lastname: Dropinski
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Conrad
authors.initials: C
authors.lastname: Santini
authors.forename: Soumya P
authors.initials: SP
authors.lastname: Sahoo
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
authors.forename: Karen L
authors.initials: KL
authors.lastname: Macnaul
authors.forename: Gaochao
authors.initials: G
authors.lastname: Zhou
authors.forename: Arun
authors.initials: A
authors.lastname: Agrawal
authors.forename: Raul
authors.initials: R
authors.lastname: Alvaro
authors.forename: Tian-Quan
authors.initials: TQ
authors.lastname: Cai
authors.forename: Melba
authors.initials: M
authors.lastname: Hernandez
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
authors.forename: David E
authors.initials: DE
authors.lastname: Moller
authors.forename: James V
authors.initials: JV
authors.lastname: Heck
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
mesh_terms: 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
chemical_list: 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