RESUMO
Directed screening has identified a novel series of non-zinc binding MMP13 inhibitors that possess good levels of activity whilst demonstrating excellent selectivity over related MMPs. A lead optimisation campaign has delivered compounds with enhanced MMP13 potency, good selectivity and acceptable bioavailability profiles leading to a predicted twice-a-day dosing regimen in man.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/farmacologia , Metaloproteinase 13 da Matriz/química , Inibidores de Metaloproteinases de Matriz , Zinco/química , Animais , Cães , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Osteoartrite/tratamento farmacológico , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
A novel, potent and selective quinazolinone series of inhibitors of p38α MAP kinase has been identified. Modifications designed to address the issues of poor aqueous solubility and high plasma protein binding as well as embedded aniline functionalities resulted in the identification of a clinical candidate N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703). Optimisation was guided by understanding of the binding modes from X-ray crystallographic studies which showed a switch from DFG 'out' to DFG 'in' as the inhibitor size was reduced to improve overall properties.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Piperazinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Proteínas Sanguíneas/química , Cristalografia por Raios X , Cães , Descoberta de Drogas , Humanos , Inflamação/tratamento farmacológico , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Peso Molecular , Piperazinas/química , Piperazinas/farmacologia , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
Directed screening has identified a novel series of MMP13 inhibitors that possess good levels of activity whilst possessing excellent selectivity over related MMPs. The binding mode of the series has been solved by co-crystallisation and demonstrates an interesting mode of inhibition without interaction with the catalytic zinc atom.
Assuntos
Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/química , Zinco/química , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Metaloproteinase 13 da Matriz/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
An imidazole series of cyclin-dependent kinase (CDK) inhibitors has been developed. Protein inhibitor structure determination has provided an understanding of the emerging structure activity trends for the imidazole series. The introduction of a methyl sulfone at the aniline terminus led to a more orally bioavailable CDK inhibitor that was progressed into clinical development.