Benzoxazinones as PPARgamma agonists. part 1: SAR of three aromatic regions

A series of benzoxazinones was synthesized as PPARgamma agonists. The compounds were obtained in seven steps, and SAR was developed by variations to the core shown below. The compounds were tested as functional agonists in the induction of the aP2 gene in preadipocytes, and the most potent compound...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2003-07, Vol.13 (14), p.2359-2362
Hauptverfasser:	Rybczynski, Philip J, Zeck, Roxanne E, Combs, Donald W, Turchi, Ignatius, Burris, Thomas P, Xu, Jun Z, Yang, Maria, Demarest, Keith T
Format:	Artikel
Sprache:	eng
Schlagworte:	Adaptor Protein Complex 2 - biosynthesis Adaptor Protein Complex 2 - genetics Adipocytes - drug effects Adipocytes - metabolism Animals Area Under Curve Biological Availability Gene Expression - drug effects Half-Life Humans Hyperglycemia - drug therapy Hyperglycemia - genetics In Vitro Techniques Indicators and Reagents Luciferases - genetics Mice Microsomes, Liver - metabolism Oxazines - chemical synthesis Oxazines - pharmacology Rats Receptors, Cytoplasmic and Nuclear - agonists Structure-Activity Relationship Subcellular Fractions Transcription Factors - agonists
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Zusammenfassung:	A series of benzoxazinones was synthesized as PPARgamma agonists. The compounds were obtained in seven steps, and SAR was developed by variations to the core shown below. The compounds were tested as functional agonists in the induction of the aP2 gene in preadipocytes, and the most potent compound in the series has an EC(50)=0.51 microM. The potency was further confirmed through a PPAR-Gal4 construct. Efficacy has been demonstrated in the db/db mouse model of hyperglycemia.
ISSN:	0960-894X