Document Detail

(2R)-2-ethylchromane-2-carboxylic acids: discovery of novel PPARalpha/gamma dual agonists as antihyperglycemic and hypolipidemic agents.
MedLine Citation:
PMID:  15163205     Owner:  NLM     Status:  MEDLINE    
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.
Hiroo Koyama; Daniel J Miller; Julia K Boueres; Ranjit C Desai; A Brian Jones; Joel P Berger; Karen L MacNaul; Linda J Kelly; Thomas W Doebber; Margaret S Wu; Gaochao Zhou; Pei-ran Wang; Marc C Ippolito; Yu-Sheng Chao; Arun K Agrawal; Ronald Franklin; James V Heck; Samuel D Wright; David E Moller; Soumya P Sahoo
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  47     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2004 Jun 
Date Detail:
Created Date:  2004-05-27     Completed Date:  2004-07-02     Revised Date:  2005-11-17    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3255-63     Citation Subset:  IM    
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065-0900, USA.
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MeSH Terms
Antilipemic Agents / chemical synthesis*,  chemistry,  pharmacokinetics,  pharmacology
Benzopyrans / chemical synthesis*,  chemistry,  pharmacokinetics,  pharmacology
Chromans / chemical synthesis*,  chemistry,  pharmacokinetics,  pharmacology
Diabetes Mellitus, Type 2 / drug therapy,  genetics
Hypoglycemic Agents / chemical synthesis*,  chemistry,  pharmacokinetics,  pharmacology
Macaca mulatta
Phenyl Ethers / chemical synthesis*,  chemistry,  pharmacokinetics,  pharmacology
Rats, Sprague-Dawley
Receptors, Cytoplasmic and Nuclear / agonists*,  genetics,  metabolism
Structure-Activity Relationship
Trans-Activators / chemical synthesis,  chemistry,  pharmacology
Transcription Factors / agonists*,  genetics,  metabolism
Reg. No./Substance:
0/7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylic acid; 0/Antilipemic Agents; 0/Benzopyrans; 0/Chromans; 0/Hypoglycemic Agents; 0/Phenyl Ethers; 0/Receptors, Cytoplasmic and Nuclear; 0/Trans-Activators; 0/Transcription Factors

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