RESUMEN

Solid-phase synthesis and SAR of alpha(V)beta(3)-receptor antagonists based on a N(1)-substituted 4-amino-1H-pyrimidin-2-one scaffold are described. The most potent compounds exhibited IC(50) values towards alpha(V)beta(3) in the nano- to subnanomolar range and high selectivity versus related integrins like alpha(IIb)beta(3). For selected examples efficacy in functional cellular assays was demonstrated.

Asunto(s)

Integrina alfaVbeta3/antagonistas & inhibidores , Pirimidinonas/síntesis química , Pirimidinonas/farmacología , Técnicas Químicas Combinatorias , Ensayo de Inmunoadsorción Enzimática , Guanidinas/farmacología , Indicadores y Reactivos , Ligandos , Imitación Molecular , Relación Estructura-Actividad

RESUMEN

A newly developed convergent solid-phase synthesis provides efficient access to thrombin inhibitors of the D-Phe-Pro-Arg type. Members of the synthesized libraries inhibited thrombin with IC(50)s in the nanomolar range.

Asunto(s)

Antitrombinas/síntesis química , Antitrombinas/metabolismo , Sitios de Unión , Cromatografía Líquida de Alta Presión , Espectrofotometría Ultravioleta , Trombina/metabolismo

RESUMEN

Solid-phase synthesis and SAR of integrin alpha(V)beta3-receptor antagonists containing a urea moiety as non-basic guanidine mimetic are described. The most potent compounds exhibited IC(50) values towards alpha(V)beta3 in the nanomolar range and high selectivity versus related integrins like alpha(IIb)beta3. For selected examples efficacy in functional cellular assays is demonstrated.

Asunto(s)

Adhesión Celular/efectos de los fármacos , Receptores de Vitronectina/antagonistas & inhibidores , Urea/análogos & derivados , Urea/síntesis química , Animales , Células CHO , Cricetinae , Diseño de Fármacos , Humanos , Modelos Moleculares , Conformación Molecular , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Relación Estructura-Actividad , Urea/farmacología