Benzoxazinones as PPARgamma agonists. 2. SAR of the amide substituent and in vivo results in a type 2 diabetes model.

Article Details

Citation

Rybczynski PJ, Zeck RE, Dudash J Jr, Combs DW, Burris TP, Yang M, Osborne MC, Chen X, Demarest KT

Benzoxazinones as PPARgamma agonists. 2. SAR of the amide substituent and in vivo results in a type 2 diabetes model.

J Med Chem. 2004 Jan 1;47(1):196-209.

PubMed ID
14695833 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
RosiglitazonePeroxisome proliferator-activated receptor gammaEC 50 (nM)120N/AN/ADetails