RESUMEN
Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.
Asunto(s)
Proteína Quinasa 10 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Animales , Barrera Hematoencefálica/efectos de los fármacos , Técnicas de Química Sintética , Cristalografía por Rayos X , Inhibidores Enzimáticos del Citocromo P-450/química , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos/métodos , Semivida , Humanos , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/metabolismo , Concentración 50 Inhibidora , Células de Riñón Canino Madin Darby/efectos de los fármacos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Proteína Quinasa 10 Activada por Mitógenos/química , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Pirazoles/química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.
Asunto(s)
Antihipertensivos/síntesis química , Hipertensión/tratamiento farmacológico , Indazoles/síntesis química , Enfermedades Renales/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides , Nitrilos/síntesis química , Animales , Antihipertensivos/farmacocinética , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Línea Celular Tumoral , Clorobencenos , Cristalografía por Rayos X , Humanos , Indazoles/farmacocinética , Indazoles/farmacología , Indenos , Masculino , Modelos Moleculares , Conformación Molecular , Nitrilos/farmacocinética , Nitrilos/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas Dahl , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A bicyclo[3.1.0]hexane, with one cyclopropane carbon flanked by a ketone and an ester or an aldehyde, undergoes methanolysis with cleavage of one of the two activated cyclopropane bonds, depending on the reaction conditions. Acidic conditions yield primarily or exclusively a 4-methoxycyclohexane, while basic conditions yield a 3-methoxymethylcyclopentanone.