RESUMO
A novel series of inhibitors for mitogen activated protein kinase-activated protein kinase 2 (MK-2) are reported. These squarate based inhibitors were identified via a high-throughput screen. An MK2 co-structure with the starting ligand was obtained and a structure based approach was followed to optimize potency and selectivity.
Assuntos
Ciclobutanos/química , Ciclobutanos/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Monócitos/citologia , Transporte Proteico , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Evaluation of selected compounds from our Corporate Compound Library in a human 5-HT(2C) receptor binding assay led to the discovery of WAY-629, a cyclohexyl[b][1,4]benzodiazepinoindole (K(i) 56 nM, E(max) 90%), which is selective for the 5-HT(2C) receptor versus other serotonin receptor subtypes, and dopamine, histamine, adrenergic, and muscarinic receptors. In addition, WAY-629 was active in vivo in a rat model of feeding behavior. An SAR study based on WAY-629 led to compound 11 (K(i) 13 nM, E(max) 102%).