RESUMEN
A series of compounds was rationally designed as inhibitors of dimer formation of the inducible isoform of nitric oxide synthase, and subsequent nitric oxide production. The conformation of two fragments obtained from a crystal structure was utilized to design a tether connecting those same two fragments. The resulting compounds were potent dimerization inhibitors that bound to the enzyme in a similar conformation as the fragments.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Sitios de Unión , Línea Celular Tumoral , Química Farmacéutica/métodos , Cristalización , Cristalografía por Rayos X , Dimerización , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Modelos Químicos , Conformación MolecularRESUMEN
A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa) inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine group that binds in the S3/S4 pocket of fXa. Introduction of a hydroxyl group para to the proximal amidine group increases the potency vs fXa by 1-2 orders of magnitude, which is the result of a hydrogen bond to Ser195 of the catalytic triad. A methyl imidazoline and a dimethylamide are good alternatives for the second amidine. These substitutions have increased the selectivity vs the related serine proteases trypsin and thrombin. The synthesis, in vitro activity, and hypothetical modes of binding to fXa based on trypsin crystallographic data are outlined.
