Design and synthesis of novel and potent amide linked PPARgamma/delta dual agonists

A series of potent amide linked PPARgamma/delta dual agonists (1a) has been discovered through rational design. In the ZDF rat model of type 2 diabetes, compound (R)-3-[4-(3-{1-[(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid (42) from this...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2007-12, Vol.17 (24), p.6744-6749
Hauptverfasser:	Shi, Qing, Canada, Emily J, Xu, Yanping, Warshawsky, Alan M, Etgen, Garret J, Broderick, Carol L, Clutinger, Cathleen K, Irwin, Lynnie A, Laurila, Michael E, Montrose-Rafizadeh, Chahrzad, Oldham, Brian A, Wang, Minmin, Winneroski, Leonard L, Xie, Chaoyu, York, Jeremy S, Yumibe, Nathan P, Zink, Richard W, Mantlo, Nathan
Format:	Artikel
Sprache:	eng
Schlagworte:	Amides - chemistry Animals Combinatorial Chemistry Techniques Diabetes Mellitus, Type 2 - drug therapy Disease Models, Animal Drug Design Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacology Molecular Structure PPAR delta - agonists PPAR gamma - agonists Rats
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Zusammenfassung:	A series of potent amide linked PPARgamma/delta dual agonists (1a) has been discovered through rational design. In the ZDF rat model of type 2 diabetes, compound (R)-3-[4-(3-{1-[(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid (42) from this series has demonstrated glucose lowering efficacy comparable to the marketed PPARgamma agonist rosiglitazone with less weight gain.
ISSN:	1464-3405