RESUMEN
The progesterone receptor is able to bind to a large number and variety of ligands that elicit a broad range of transcriptional responses ranging from full agonism to full antagonism and numerous mixed profiles inbetween. We describe here two new progesterone receptor ligand binding domain x-ray structures bound to compounds from a structurally related but functionally divergent series, which show different binding modes corresponding to their agonistic or antagonistic nature. In addition, we present a third progesterone receptor ligand binding domain dimer bound to an agonist in monomer A and an antagonist in monomer B, which display binding modes in agreement with the earlier observation that agonists and antagonists from this series adopt different binding modes.
Asunto(s)
Receptores de Progesterona/agonistas , Receptores de Progesterona/antagonistas & inhibidores , Receptores de Progesterona/metabolismo , Animales , Sitios de Unión , Células CHO , Cricetinae , Cricetulus , Cristalografía por Rayos X/métodos , Dimerización , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Ligandos , Mifepristona/química , Modelos Moleculares , Conformación Molecular , Noretindrona/química , Progesterona/química , Unión Proteica , Conformación ProteicaRESUMEN
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
High-throughput screening of 3.87 million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist.