Design and biological evaluation of novel, balanced dual PPARalpha/gamma agonists

An X-ray-guided design approach led to the identification of a novel, balanced class of alpha-ethoxy-phenylpropionic acid-derived dual PPARalpha/gamma agonists. The series shows a wide range of PPARalpha/gamma ratios within a rather narrow structural space. Advanced compounds possess favorable physi...

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Veröffentlicht in:	ChemMedChem 2009-06, Vol.4 (6), p.951-956
Hauptverfasser:	Grether, Uwe, Bénardeau, Agnes, Benz, Jörg, Binggeli, Alfred, Blum, Denise, Hilpert, Hans, Kuhn, Bernd, Märki, Hans Peter, Meyer, Markus, Mohr, Peter, Püntener, Kurt, Raab, Susanne, Ruf, Armin, Schlatter, Daniel
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Computer Simulation Crystallography, X-Ray Diabetes Mellitus, Type 2 - drug therapy Drug Design Humans Hypolipidemic Agents - chemical synthesis Hypolipidemic Agents - chemistry Hypolipidemic Agents - pharmacokinetics Mice Phenylpropionates - chemical synthesis Phenylpropionates - chemistry Phenylpropionates - pharmacokinetics PPAR alpha - agonists PPAR alpha - metabolism PPAR gamma - agonists PPAR gamma - metabolism Rats Stereoisomerism Structure-Activity Relationship
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Zusammenfassung:	An X-ray-guided design approach led to the identification of a novel, balanced class of alpha-ethoxy-phenylpropionic acid-derived dual PPARalpha/gamma agonists. The series shows a wide range of PPARalpha/gamma ratios within a rather narrow structural space. Advanced compounds possess favorable physicochemical and pharmacokinetic profiles and show a high efficacy in T2D and dyslipidemia animal models.
ISSN:	1860-7187
DOI:	10.1002/cmdc.200800425