RESUMEN
A novel series of pyrrolidine heterocycles was prepared and found to show potent inhibitory activity of CCR1 binding and CCL3 mediated chemotaxis of a CCR1-expressing cell line. A potent, optimized triazole lead from this series was found to have acceptable pharmacokinetics and microsomal stability in rat and is suitable for further optimization and development.
Asunto(s)
Quimiocina CCL3/inmunología , Quimiotaxis/efectos de los fármacos , Pirrolidinas/química , Pirrolidinas/farmacología , Receptores CCR1/antagonistas & inhibidores , Animales , Línea Celular , Microsomas Hepáticos/metabolismo , Pirrolidinas/metabolismo , Pirrolidinas/farmacocinética , Ratas , Receptores CCR1/inmunología , Triazoles/química , Triazoles/metabolismo , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.
RESUMEN
Properly substituted pyrazolo[1,5-a]pyrimidines are potent and selective CDK2 inhibitors. Compound 15j is orally available and showed efficacy in a mouse A2780 xenograft model.
Asunto(s)
Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Pirazoles/química , Pirazoles/farmacología , Piridinas/química , Piridinas/farmacología , Administración Oral , Animales , Cristalografía por Rayos X , Quinasa 2 Dependiente de la Ciclina/efectos de los fármacos , Perros , Ensayos de Selección de Medicamentos Antitumorales , Haplorrinos , Ratones , Modelos Animales , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Piridinas/síntesis química , Ratas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
By the screening of a combinatorial library for inhibitors of nitric oxide (NO) formation by the inducible isoform of nitric oxide synthase (iNOS) using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were found to inhibit the dimerization of iNOS monomers, thus preventing the formation of the dimeric, active form of the enzyme. Optimization led to the selection of the potent, selective, and orally available iNOS dimerization inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a rat model. Analysis of the crystal structure of the 21b--iNOS monomer complex provided a rationalization for both the SAR and the mechanism by which 21b blocks the formation of the protein--protein interaction present in the dimeric form of iNOS.
