RESUMO
We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.
Assuntos
Benzenoacetamidas/química , Benzenoacetamidas/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Epilepsia Generalizada/tratamento farmacológico , Animais , Benzenoacetamidas/metabolismo , Benzenoacetamidas/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Bloqueadores dos Canais de Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacocinética , Cães , Descoberta de Drogas , Epilepsia Generalizada/metabolismo , Cobaias , Humanos , Macaca fascicularis , Pirazóis/química , Pirazóis/farmacologia , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
We describe the discovery and optimization of new, brain-penetrant T-type calcium channel blockers. We present optimized compounds with excellent efficacy in a rodent model of generalized absence-like epilepsy. Along the fine optimization of a chemical series with a pharmacological target located in the CNS (target potency, brain penetration, and solubility), we successfully identified an Ames negative aminopyrazole as putative metabolite of this compound series. Our efforts culminated in the selection of compound 20, which was elected as a preclinical candidate.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo T/efeitos dos fármacos , Descoberta de Drogas , Epilepsia Generalizada/tratamento farmacológico , Animais , Canais de Cálcio Tipo T/fisiologia , Modelos Animais de Doenças , Humanos , Camundongos , RatosRESUMO
We identified and characterized a series of pyrrole amides as potent, selective Cav3.2-blockers. This series culminated with the identification of pyrrole amides 13b and 26d, with excellent potencies and/or selectivities toward the Cav3.1- and Cav3.3-channels. These compounds display poor physicochemical and DMPK properties, making their use difficult for in vivo applications. Nevertheless, they are well-suited for in vitro studies.
Assuntos
Amidas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Descoberta de Drogas , Pirróis/farmacologia , Amidas/síntese química , Amidas/química , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Ratos , Relação Estrutura-AtividadeRESUMO
We identified and characterized a series of pyrazole amides as potent, selective Cav3.1-blockers. This series culminated with the identification of pyrazole amides 5a and 12d, with excellent potencies and/or selectivities toward the Cav3.2- and Cav3.3-channels. This compound displays poor DMPK properties, making its use difficult for in vivo applications. Nevertheless, this compound as well as analogous ones are well-suited for in vitro studies.
Assuntos
Amidas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Descoberta de Drogas , Pirróis/farmacologia , Amidas/síntese química , Amidas/química , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Ratos , Relação Estrutura-AtividadeRESUMO
Macitentan, also called Actelion-1 or ACT-064992 [N-[5-(4-bromophenyl)-6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)-pyrimidin-4-yl]-N'-propylaminosulfonamide], is a new dual ET(A)/ET(B) endothelin (ET) receptor antagonist designed for tissue targeting. Selection of macitentan was based on inhibitory potency on both ET receptors and optimization of physicochemical properties to achieve high affinity for lipophilic milieu. In vivo, macitentan is metabolized into a major and pharmacologically active metabolite, ACT-132577. Macitentan and its metabolite antagonized the specific binding of ET-1 on membranes of cells overexpressing ET(A) and ET(B) receptors and blunted ET-1-induced calcium mobilization in various natural cell lines, with inhibitory constants within the nanomolar range. In functional assays, macitentan and ACT-132577 inhibited ET-1-induced contractions in isolated endothelium-denuded rat aorta (ET(A) receptors) and sarafotoxin S6c-induced contractions in isolated rat trachea (ET(B) receptors). In rats with pulmonary hypertension, macitentan prevented both the increase of pulmonary pressure and the right ventricle hypertrophy, and it markedly improved survival. In diabetic rats, chronic administration of macitentan decreased blood pressure and proteinuria and prevented end-organ damage (renal vascular hypertrophy and structural injury). In conclusion, macitentan, by its tissue-targeting properties and dual antagonism of ET receptors, protects against end-organ damage in diabetes and improves survival in pulmonary hypertensive rats. This profile makes macitentan a new agent to treat cardiovascular disorders associated with chronic tissue ET system activation.