title: (2R)-2-ethylchromane-2-carboxylic acids: discovery of novel PPARalpha/gamma dual agonists as antihyperglycemic and hypolipidemic agents.
abstract: A series of chromane-2-carboxylic acid derivatives was synthesized and evaluated for PPAR agonist activities. A structure-activity relationship was developed toward PPARalpha/gamma dual agonism. As a result, (2R)-7-(3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy)-2-ethylchromane-2-carboxylic acid (48) was identified as a potent, structurally novel, selective PPARalpha/gamma dual agonist. Compound 48 exhibited substantial antihyperglycemic and hypolipidemic activities when orally administered in three different animal models: the db/db mouse type 2 diabetes model, a Syrian hamster lipid model, and a dog lipid model.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065-0900, USA. hiroo_koyama@merck.com
authors.forename: Hiroo
authors.initials: H
authors.lastname: Koyama
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Miller
authors.forename: Julia K
authors.initials: JK
authors.lastname: Boueres
authors.forename: Ranjit C
authors.initials: RC
authors.lastname: Desai
authors.forename: A Brian
authors.initials: AB
authors.lastname: Jones
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
authors.forename: Karen L
authors.initials: KL
authors.lastname: MacNaul
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Kelly
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Doebber
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Wu
authors.forename: Gaochao
authors.initials: G
authors.lastname: Zhou
authors.forename: Pei-ran
authors.initials: PR
authors.lastname: Wang
authors.forename: Marc C
authors.initials: MC
authors.lastname: Ippolito
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Arun K
authors.initials: AK
authors.lastname: Agrawal
authors.forename: Ronald
authors.initials: R
authors.lastname: Franklin
authors.forename: James V
authors.initials: JV
authors.lastname: Heck
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
authors.forename: David E
authors.initials: DE
authors.lastname: Moller
authors.forename: Soumya P
authors.initials: SP
authors.lastname: Sahoo
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002839:Chromans / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006224:Cricetinae; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics; D004285:Dogs; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D008647:Mesocricetus; D051379:Mice; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: C487415:7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylic acid; D001578:Benzopyrans; D002839:Chromans; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D010647:Phenyl Ethers; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors