RESUMEN
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.
Asunto(s)
Aminas/química , Isoquinolinas/química , Piperidinas/química , Inhibidores de Proteínas Quinasas/química , Quinolonas/química , Quinasas Asociadas a rho/antagonistas & inhibidores , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/uso terapéutico , Aminas/síntesis química , Aminas/uso terapéutico , Animales , Modelos Animales de Enfermedad , Hipertensión/tratamiento farmacológico , Modelos Químicos , Modelos Moleculares , Piperidinas/síntesis química , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolonas/síntesis química , Quinolonas/uso terapéutico , Ratas , Relación Estructura-Actividad , Quinasas Asociadas a rho/metabolismoRESUMEN
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.
Asunto(s)
Aminas/química , Isoquinolinas/química , Inhibidores de Proteínas Quinasas/química , Quinasas Asociadas a rho/antagonistas & inhibidores , Aminas/síntesis química , Aminas/farmacocinética , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Isoquinolinas/síntesis química , Isoquinolinas/farmacocinética , Ratones , Ratones Endogámicos C57BL , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Relación Estructura-Actividad , Quinasas Asociadas a rho/metabolismoRESUMEN
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.
Asunto(s)
Catepsina K/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/química , Triazinas/química , Sitios de Unión , Dominio Catalítico , Catepsina K/metabolismo , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/farmacología , Ensayos Analíticos de Alto Rendimiento , Humanos , Relación Estructura-Actividad , Triazinas/síntesis química , Triazinas/farmacología , Uracilo/análogos & derivados , Uracilo/síntesis química , Uracilo/química , Uracilo/farmacologíaRESUMEN
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.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Nitrilos/química , Inhibidores de Proteasas/química , Purinas/química , Dominio Catalítico , Catepsina K/antagonistas & inhibidores , Catepsina K/metabolismo , Catepsinas/metabolismo , Línea Celular , Simulación por Computador , Humanos , Nitrilos/síntesis química , Nitrilos/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Purinas/síntesis química , Purinas/farmacología , Pirimidinas/químicaRESUMEN
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.