Benzoxazinones as PPARgamma agonists. 2. SAR of the amide substituent and in vivo results in a type 2 diabetes model.
J Med Chem
; 47(1): 196-209, 2004 Jan 01.
Article
em En
| MEDLINE
| ID: mdl-14695833
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oxazinas
/
Fatores de Transcrição
/
Receptores Citoplasmáticos e Nucleares
/
Diabetes Mellitus Tipo 2
/
Amidas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Ano de publicação:
2004
Tipo de documento:
Article