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 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.
Rybczynski
Philip J
PJ
Johnson and Johnson Pharmaceutical Research and Development, LLC, 08869, Raritan, NJ, USA. prybczyn@prdus.jnj.com
Zeck
Roxanne E
RE
Combs
Donald W
DW
Turchi
Ignatius
I
Burris
Thomas P
TP
Xu
Jun Z
JZ
Yang
Maria
M
Demarest
Keith T
KT
D033962:Adaptor Protein Complex 2 / Q000096:biosynthesis / Q000235:genetics; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D015870:Gene Expression / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000235:genetics; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions; D014157:Transcription Factors / Q000819:agonists*
D033962:Adaptor Protein Complex 2; D007202:Indicators and Reagents; D010078:Oxazines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D008156:Luciferases