RESUMO
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.
Assuntos
Proteína Quinase 10 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Técnicas de Química Sintética , Cristalografia por Raios X , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Meia-Vida , Humanos , Doença de Huntington/tratamento farmacológico , Doença de Huntington/metabolismo , Concentração Inibidora 50 , Células Madin Darby de Rim Canino/efeitos dos fármacos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Proteína Quinase 10 Ativada por Mitógeno/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Pirazóis/química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Anti-Hipertensivos/síntese química , Hipertensão/tratamento farmacológico , Indazóis/síntese química , Nefropatias/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides , Nitrilas/síntese química , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular Tumoral , Clorobenzenos , Cristalografia por Raios X , Humanos , Indazóis/farmacocinética , Indazóis/farmacologia , Indenos , Masculino , Modelos Moleculares , Conformação Molecular , Nitrilas/farmacocinética , Nitrilas/farmacologia , Ensaio Radioligante , Ratos , Ratos Endogâmicos Dahl , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.