RESUMO
In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.
Assuntos
2-Aminopurina/química , 2-Aminopurina/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Purinas/química , Traumatismo por Reperfusão/enzimologia , Animais , Domínio Catalítico , Cães , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Haplorrinos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Purinas/farmacologia , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF.
