(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 (4...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2004-06, Vol.47 (12), p.3255-3263
Main Authors: Koyama, Hiroo, Miller, Daniel J, Boueres, Julia K, Desai, Ranjit C, Jones, A Brian, Berger, Joel P, MacNaul, Karen L, Kelly, Linda J, Doebber, Thomas W, Wu, Margaret S, Zhou, Gaochao, Wang, Pei-ran, Ippolito, Marc C, Chao, Yu-Sheng, Agrawal, Arun K, Franklin, Ronald, Heck, James V, Wright, Samuel D, Moller, David E, Sahoo, Soumya P
Format: Article
Language:English
Subjects:
Animals
Benzopyrans - chemical synthesis
Benzopyrans - chemistry
Benzopyrans - pharmacokinetics
Benzopyrans - pharmacology
Chromans - chemical synthesis
Chromans - chemistry
Chromans - pharmacokinetics
Chromans - pharmacology
Cricetinae
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - genetics
Dogs
Humans
Hypoglycemic Agents - chemical synthesis
Hypoglycemic Agents - chemistry
Hypoglycemic Agents - pharmacokinetics
Hypoglycemic Agents - pharmacology
Hypolipidemic Agents - chemical synthesis
Hypolipidemic Agents - chemistry
Hypolipidemic Agents - pharmacokinetics
Hypolipidemic Agents - pharmacology
Macaca mulatta
Male
Mesocricetus
Mice
Phenyl Ethers - chemical synthesis
Phenyl Ethers - chemistry
Phenyl Ethers - pharmacokinetics
Phenyl Ethers - pharmacology
Rats
Rats, Sprague-Dawley
Receptors, Cytoplasmic and Nuclear - agonists
Receptors, Cytoplasmic and Nuclear - genetics
Receptors, Cytoplasmic and Nuclear - metabolism
Stereoisomerism
Structure-Activity Relationship
Trans-Activators - chemical synthesis
Trans-Activators - chemistry
Trans-Activators - pharmacology
Transcription Factors - agonists
Transcription Factors - genetics
Transcription Factors - metabolism
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Summary: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.
ISSN:0022-2623