(2R)-2-ethylchromane-2-carboxylic acids: discovery of novel PPARalpha/gamma dual agonists as antihyperglycemic and hypolipidemic agents.
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.
Koyama
Hiroo
H
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065-0900, USA. hiroo_koyama@merck.com
Miller
Daniel J
DJ
Boueres
Julia K
JK
Desai
Ranjit C
RC
Jones
A Brian
AB
Berger
Joel P
JP
MacNaul
Karen L
KL
Kelly
Linda J
LJ
Doebber
Thomas W
TW
Wu
Margaret S
MS
Zhou
Gaochao
G
Wang
Pei-ran
PR
Ippolito
Marc C
MC
Chao
Yu-Sheng
YS
Agrawal
Arun K
AK
Franklin
Ronald
R
Heck
James V
JV
Wright
Samuel D
SD
Moller
David E
DE
Sahoo
Soumya P
SP
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
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