RESUMEN
High-throughput screening is routinely employed as a method for the identification of novel hit structures. Large numbers of active compounds are typically procured in this way and must undergo a rigorous validation process. This process is described in detail for a collection of screening hits identified as inhibitors of IkappaB kinase-beta (IKKbeta), a key regulatory enzyme in the nuclear factor-kappaB (NF-kappaB) pathway. From these studies, a promising hit series was selected. Subsequent lead generation activities included the development of a pharmacophore hypothesis and structure-activity relationship (SAR) for the hit series. This led to the exploration of related scaffolds offering additional opportunities, and the various structural classes were comparatively evaluated for enzyme inhibition, selectivity, and drug-like properties. A novel lead series of thienopyridines was thereby established, and this series advanced into lead optimization for further development.
Asunto(s)
Quinasa I-kappa B/antagonistas & inhibidores , Quinasa I-kappa B/química , Modelos Moleculares , Piridinas/síntesis química , Oxazoles/síntesis química , Oxazoles/química , Piridinas/química , Relación Estructura-ActividadRESUMEN
The specificity of the immune response relies on processing of foreign proteins and presentation of antigenic peptides at the cell surface. Inhibition of antigen presentation, and the subsequent activation of T-cells, should, in theory, modulate the immune response. The cysteine protease Cathepsin S performs a fundamental step in antigen presentation and therefore represents an attractive target for inhibition. Herein, we report a series of potent and reversible Cathepsin S inhibitors based on dipeptide nitriles. These inhibitors show nanomolar inhibition of the target enzyme as well as cellular potency in a human B cell line. The first X-ray crystal structure of a reversible inhibitor cocrystallized with Cathepsin S is also reported.
Asunto(s)
Catepsinas/síntesis química , Dipéptidos/síntesis química , Inhibidores Enzimáticos/síntesis química , Nitrilos/síntesis química , Linfocitos B/efectos de los fármacos , Unión Competitiva , Catepsinas/química , Catepsinas/farmacología , Línea Celular , Cristalografía por Rayos X , Dipéptidos/química , Dipéptidos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Cinética , Modelos Moleculares , Nitrilos/química , Nitrilos/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
[reaction: see text] A new sequence for the synthesis of various 2,4-disubstituted oxazoles from alpha-amino acids is reported. The method is shown to be general and incorporates the reagent combination, triphenylphosphine/hexachloroethane, for cyclodehydration of intermediate alpha-acylamino aldehydes. Implementation of this reagent system for the conversion of alpha-acylamino ketones to oxazoles is briefly investigated.