RESUMEN
We describe a series of pyrazole and isoxazole analogs as antagonists of the alpha(v)beta3 receptor. Compounds showed low to sub-nanomolar potency against alpha(v)beta3, as well as good selectivity against alpha(IIb)beta3. In HT29 cells, most analogs also demonstrated significant selectivity against alpha(v)beta6. Several compounds showed good pharmacokinetic properties in rats, in addition to anti-angiogenic activity in a mouse corneal micropocket model. Compounds were synthesized in a straightforward manner from readily available glutarate precursors.
Asunto(s)
Integrina alfaVbeta3/antagonistas & inhibidores , Isoxazoles/síntesis química , Isoxazoles/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Animales , Línea Celular , Humanos , Integrina alfaVbeta3/metabolismo , Isoxazoles/química , Isoxazoles/farmacocinética , Ratones , Estructura Molecular , Pirazoles/química , Pirazoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
We describe a series of 1,2,4-oxadiazoles, which are potent antagonists of the integrin alpha(v)beta3 and, in addition, show selectivity relative to the other beta3 integrin alpha(IIb)beta3. In whole cells, the majority of these analogs also demonstrated modest selectivity against other alpha(v) integrins such as alpha(v)beta1 and alpha(v)beta6.
Asunto(s)
Butiratos/síntesis química , Butiratos/farmacología , Integrina alfaVbeta3/antagonistas & inhibidores , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Antígenos de Neoplasias , Butiratos/química , Línea Celular , Humanos , Integrinas/antagonistas & inhibidores , Estructura Molecular , Oxadiazoles/química , Receptores de Vitronectina/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
We describe a series of 2,5 thiazole containing compounds, which are potent antagonists of the integrin alpha(v)beta3 and show selectivity relative to the other integrins, such as alpha(IIb)beta3 and alpha(v)beta6. These analogs were demonstrated to have high bioavailability relative to other relative heterocyclic analogs.
Asunto(s)
Butiratos/síntesis química , Butiratos/farmacocinética , Integrina alfaVbeta3/antagonistas & inhibidores , Tiazoles/síntesis química , Tiazoles/farmacocinética , Administración Oral , Animales , Antígenos de Neoplasias , Disponibilidad Biológica , Butiratos/administración & dosificación , Perros , Evaluación Preclínica de Medicamentos , Haplorrinos , Integrinas/antagonistas & inhibidores , Estructura Molecular , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Ratas , Relación Estructura-Actividad , Tiazoles/administración & dosificaciónRESUMEN
We describe a series of conformationally-restricted cinnamic acid peptidomimetics as well as several cinnamic acid isosteres, including 3-phenylpropionic acids, 2-amino-3-phenylpropionic acids, phenoxyacetic acids and 2-phenylcyclopropylcarboxylic acids. Several analogues demonstrated low to sub-nanomolar potencies against alpha(v)beta(3) and greater than 200-fold selectivity against the other beta(3) integrin alpha(IIb)beta(3). In whole 293 cells, many of these analogues also showed modest selectivity against other alpha(v) integrins such as alpha(v)beta(1) and alpha(v)beta(5). These compounds were synthesized from readily available starting materials using either Heck or Mitsunobu coupling conditions.