RESUMEN
High-throughput screening has identified 1-methyl-3-(trifluoromethyl)-N-[4-(pyrrolidinylsulfonyl)phenyl]-1H-pyrazole-5-carboxamide 16677 as a novel and potent (IC(50)=35-145 nM) inhibitor against multiple primary isolates of diverse measles virus (MV) genotypes currently circulating worldwide. The synthesis of 16677 and several analogs together with effects on MV replication is described. The most potent analog displays nanomolar inhibition against the MV and a selectivity ratio (CC(50)/IC(50)) of ca. 16,500.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Virus del Sarampión/enzimología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Técnicas In Vitro , 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
The synthesis and biological evaluation of a series of heterocyclic analogues of the previously reported LTA(4) hydrolase inhibitor 1b are described. Imidazopyridine and purine analogues are specifically highlighted with several demonstrating excellent potency in our in vitro assays, as well as good oral activity in a mouse ex vivo assay.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Epóxido Hidrolasas/antagonistas & inhibidores , Purinas/síntesis química , Purinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Animales , Epóxido Hidrolasas/sangre , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Humanos , Técnicas In Vitro , Indicadores y Reactivos , Ratones , Proteínas Recombinantes/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
The synthesis and biological evaluation of a series of functionalized pyrrolidine- and piperidine-containing analogues of our lead LTA(4) hydrolase inhibitor, SC-57461A, is described. A number of compounds showed excellent potency in our in vitro screens and several demonstrated good oral activity in a mouse ex vivo assay. These efforts led to the identification of SC-56938 (14) as a potent, orally active inhibitor of LTA(4) hydrolase.