Conformationally constrained ortho-anilino diaryl ureas: discovery of 1-(2-(1'-neopentylspiro[indoline-3,4'-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a potent, selective, and bioavailable P2Y1 antagonist.
J Med Chem
; 56(22): 9275-95, 2013 Nov 27.
Article
em En
| MEDLINE
| ID: mdl-24164581
ABSTRACT
Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Compostos de Fenilureia
/
Compostos de Espiro
/
Ureia
/
Desenho de Fármacos
/
Receptores Purinérgicos P2Y1
/
Antagonistas do Receptor Purinérgico P2Y
/
Conformação Molecular
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article