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.
Assuntos
Cicloexanóis/química , Cicloexanóis/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , MAP Quinase Quinase 4/antagonistas & inibidores , Purinas/química , Purinas/farmacologia , Administração Oral , Animais , Domínio Catalítico , Cicloexanóis/administração & dosagem , Cães , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Haplorrinos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Purinas/administração & dosagem , Ratos , Relação Estrutura-AtividadeRESUMO
Autoantibodies and the immunoreceptors to which they bind can contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). Spleen Tyrosine Kinase (Syk) is a non-receptor tyrosine kinase with a central role in immunoreceptor (FcR) signaling and immune cell functionality. Syk kinase inhibitors have activity in antibody-dependent immune cell activation assays, in preclinical models of arthritis, and have progressed into clinical trials for RA and other autoimmune diseases. Here we describe the characterization of a novel triazolopyridine-based Syk kinase inhibitor, CC-509. This compound is a potent inhibitor of purified Syk enzyme, FcR-dependent and FcR-independent signaling in primary immune cells, and basophil activation in human whole blood. CC-509 is moderately selective across the kinome and against other non-kinase enzymes or receptors. Importantly, CC-509 was optimized away from and has modest activity against cellular KDR and Jak2, kinases that when inhibited in a preclinical and clinical setting may promote hypertension and neutropenia, respectively. In addition, CC-509 is orally bioavailable and displays dose-dependent efficacy in two rodent models of immune-inflammatory disease. In passive cutaneous anaphylaxis (PCA), CC-509 significantly inhibited skin edema. Moreover, CC-509 significantly reduced paw swelling and the tissue levels of pro-inflammatory cytokines RANTES and MIP-1α in the collagen-induced arthritis (CIA) model. In summary, CC-509 is a potent, moderately selective, and efficacious inhibitor of Syk that has a differentiated profile when compared to other Syk compounds that have progressed into the clinic for RA.