RESUMEN
Starting with lead compound 2, we sought to increase the selectivity for alpha(v)beta(3)-mediated cell adhesion by examining the effects of structural changes in both the guanidine mimetic and the substituent alpha to the carboxylate. To prepare some of the desired aminoimidazoles, a novel reductive amination utilizing a trityl-protected aminoimidazole was developed. It was found that guanidine mimetics with a wide range of pK(a)'s were potent antagonists of alpha(v)beta(3). In general, it appeared that an acylated 2-aminoimidazole guanidine mimetic imparted excellent selectivity for alpha(v)beta(3)-mediated adhesion versus alpha(IIb)beta(3)-mediated platelet aggregation, with selectivity of approximately 3 orders of magnitude observed for compounds 3g and 3h. It was also found in this series that the alpha-substituent was required for potent activity and that 2,6-disubstituted arylsulfonamides were optimal. In addition, the selective alpha(v)beta(3) antagonist 3h was found to be a potent inhibitor of alpha(v)beta(3)-mediated cell migration.
Asunto(s)
Isoxazoles/síntesis química , Receptores de Vitronectina/antagonistas & inhibidores , beta-Alanina/análogos & derivados , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Quimiotaxis/efectos de los fármacos , Guanidinas/química , Humanos , Hiperplasia/metabolismo , Técnicas In Vitro , Isoxazoles/química , Isoxazoles/farmacología , Riñón/citología , Riñón/efectos de los fármacos , Riñón/metabolismo , Agregación Plaquetaria/efectos de los fármacos , Receptores de Vitronectina/biosíntesis , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales Cultivadas , Vitronectina/farmacología , beta-Alanina/síntesis química , beta-Alanina/química , beta-Alanina/farmacologíaRESUMEN
The structure-activity relationships of some tetracyclic heterocycles related to Brequinar were explored. Activities as inhibitors of dihydroorotate dehydrogenase and the mixed lymphocyte reaction are related to ring system, heteroatom placement, and pendant ring substitution.
Asunto(s)
Compuestos de Bifenilo/química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Inmunosupresores/química , Inmunosupresores/farmacología , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Dihidroorotato Deshidrogenasa , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Prueba de Cultivo Mixto de Linfocitos , Oxidorreductasas/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
The discovery of terphenyl derivatives as highly selective COX-2 inhibitors resulted from our efforts to overcome poor pharmacokinetics demonstrated by the COX-2 selective diarylthiophene DuP 697 [2-bromo-4-(4'-sulfonylmethyl)phenyl-5-(4'-fluoro)phenylthiophe ne]. Detailed SAR related to the ortho-biphenyls and variants of the central ring are described herein.