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A series of benzoxazinones has been synthesized and tested for PPARgamma agonist activity. Synthetic approaches were developed to provide either racemic or chiral compounds. In vitro functional potency could be measured through induction of the aP2 gene, a target of PPARgamma. These studies revealed that compounds with large aliphatic chains at the nitrogen of the benzoxazinone were the most potent. Substitution of the chain was tolerated and in many cases enhanced the in vitro potency of the compound. Select compounds were further tested for metabolic stability, oral bioavailability in rats, and efficacy in db/db mice after 11 days of dosing. In vivo analysis with 13 and 57 demonstrated that the series has potential for the treatment of type 2 diabetes.

Enzyme inhibiting activity X 0220 Synthesis and Evaluation of 3-Anilino-quinoxalinones as Glycogen Phosphorylase Inhibitors. -Some of the novel substances are 25 times more potent then the original hit [cf. derivatives (Ia) and (Ib)]. -(DUDASH*, J. J.; ZHANG, Y.; MOORE, J. B.; LOOK, R.; LIANG, Y.; BEAVERS, M. P.; CONWAY, B. R.; RYBCZYNSKI, P. J.; DEMAREST, K. T.; Bioorg. Med. Chem. Lett. 15 (2005) 21, 4790-4793; Johnson and Johnson Pharm. Res. Dev., Raritan, NJ 08869, USA; Eng.) -K. Schneider 05-234