RESUMO
Rho kinase is an important target implicated in a variety of cardiovascular diseases. Herein, we report the optimisation of the fragment derived ATP-competitive ROCK inhibitors 1 and 2 into lead compound 14A. The initial goal of improving ROCK-I potency relative to 1, whilst maintaining a good PK profile, was achieved through removal of the aminoisoquinoline basic centre. Lead 14A was equipotent against both ROCK-I and ROCK-II, showed good in vivo efficacy in the spontaneous hypertensive rat model, and was further optimised to demonstrate the scope for improving selectivity over PKA versus hydroxy Fasudil 3.
Assuntos
Aminas/química , Isoquinolinas/química , Piperidinas/química , Inibidores de Proteínas Quinases/química , Quinolonas/química , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Aminas/síntese química , Aminas/uso terapêutico , Animais , Modelos Animais de Doenças , Hipertensão/tratamento farmacológico , Modelos Químicos , Modelos Moleculares , Piperidinas/síntese química , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Quinolonas/síntese química , Quinolonas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismoRESUMO
Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.
Assuntos
Aminas/química , Isoquinolinas/química , Inibidores de Proteínas Quinases/química , Quinases Associadas a rho/antagonistas & inibidores , Aminas/síntese química , Aminas/farmacocinética , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismoRESUMO
A novel dioxo-triazine series of cathepsin K inhibitors was identified from HTS. A rapid exploratory programme led to the discovery of potent and selective cathepsin K inhibitors, typified by compound 24 which displayed IC(50) values of 17nM against catK and >10,000nM in catL, catB and catS assays.
Assuntos
Catepsina K/antagonistas & inibidores , Inibidores de Cisteína Proteinase/química , Triazinas/química , Sítios de Ligação , Domínio Catalítico , Catepsina K/metabolismo , Cristalografia por Raios X , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/farmacologia , Uracila/análogos & derivados , Uracila/síntese química , Uracila/química , Uracila/farmacologiaRESUMO
Starting from previously disclosed equally potent cathepsin K and S inhibitor 4-propyl-6-(3-trifluoromethylphenyl)pyrimidine-2-carbonitrile 1, a novel 2-phenyl-9H-purine-6-carbonitrile scaffold was identified to provide potent and selective cathepsin S inhibitors.
Assuntos
Catepsinas/antagonistas & inibidores , Nitrilas/química , Inibidores de Proteases/química , Purinas/química , Domínio Catalítico , Catepsina K/antagonistas & inibidores , Catepsina K/metabolismo , Catepsinas/metabolismo , Linhagem Celular , Simulação por Computador , Humanos , Nitrilas/síntese química , Nitrilas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Purinas/síntese química , Purinas/farmacologia , Pirimidinas/químicaRESUMO
6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile analogues were identified as potent and selective cathepsin S inhibitor against both purified enzyme and in human JY cell based cellular assays. This core has a very stable thio-trapping nitrile war-head in comparison with the well reported pyrimidine-2-carbonitrile cysteine cathepsin inhibitors. Compound 47 is also very potent in in vivo mouse spleenic Lip10 accumulation assays.