Benzoxazinones as PPARγ Agonists. 2. SAR of the Amide Substituent and In Vivo Results in a Type 2 Diabetes Model

• Published in: Journal of medicinal chemistry Vol. 47; no. 1; pp. 196 - 209
• Main Authors: Rybczynski, Philip J, Zeck, Roxanne E, Dudash, Joseph, Combs, Donald W, Burris, Thomas P, Yang, Maria, Osborne, Melville C, Chen, Xiaoli, Demarest, Keith T
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.01.2004; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; ACTIVATED RECEPTOR-GAMMA; LIPID-METABOLISM; PIOGLITAZONE; INSULIN-RESISTANCE; AGENTS; J; OPTIMIZATION; MECHANISMS; MELLITUS; DIFFERENTIATION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0301888

A series of benzoxazinones has been synthesized and tested for PPARγ 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 PPARγ. 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.