RESUMO
Structure-activity relationship studies directed toward improving the metabolic stability of compound 1 resulted in the identification of 3-[5-(3,5-difluorophenyl)-3-({[(1S,3R)-3-fluorocyclopentyl]amino}methyl)-4-methyl-1H-pyrazol-1-yl]propanenitrile 39 (MK-1925) as a selective, orally available and brain-penetrable opioid receptor-like 1 (ORL1) antagonist. The compound also showed in vivo efficacy after oral dosing. Therefore, compound 39 was selected to undergo further studies as a clinical candidate.
Assuntos
Encéfalo/metabolismo , Antagonistas de Entorpecentes , Nitrilas/química , Pirazóis/química , Administração Oral , Animais , Humanos , Camundongos , Nitrilas/administração & dosagem , Nitrilas/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Ratos , Receptores Opioides/metabolismo , Relação Estrutura-Atividade , Receptor de NociceptinaRESUMO
The synthesis and evaluation of a series of 2,4-diaminopyridine-based neuropeptide Y Y1 (NPY Y1) receptor antagonists are described. Compound 1 was previously reported by our laboratory to be a potent and selective Y1 antagonist; however, 1 was also found to have potent hERG inhibitory activity. The main focus of this communication is structure-activity relationship development aimed at eliminating the hERG activity of 1. This resulted in the identification of compound 3d as a potent and selective NPY Y1 antagonist with reduced hERG liability.
Assuntos
4-Aminopiridina/análogos & derivados , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Receptores de Neuropeptídeo Y/antagonistas & inibidores , 4-Aminopiridina/química , Animais , Células CHO , Linhagem Celular , Química Farmacêutica/métodos , Cricetinae , Cricetulus , Desenho de Fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/química , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Modelos Químicos , Receptores de Neuropeptídeo Y/química , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
The synthesis and biological evaluation of new potent opioid receptor-like 1 antagonists are presented. A structure-activity relationship (SAR) study of arylpyrazole lead compound 1 obtained from library screening identified compound 31, (1S,3R)-N-{[1-(3-chloropyridin-2-yl)-5-(5-fluoro-6-methylpyridin-3-yl)-4-methyl-1H-pyrazol-3-yl]methyl}-3-fluorocyclopentanamine, which exhibits high intrinsic potency and selectivity against other opioid receptors and hERG potassium channel.
Assuntos
Ciclopentanos/química , Antagonistas de Entorpecentes , Pirazóis/química , Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Descoberta de Drogas , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Pirazóis/síntese química , Pirazóis/farmacologia , Receptores Opioides/metabolismo , Relação Estrutura-Atividade , Receptor de NociceptinaRESUMO
A series of compounds based on 7-{[4-(2-methylphenyl)piperidin-1-yl]methyl}-6,7,8,9-tetrahydro-5 H-cyclohepta[ b]pyridine-9-ol ( (-)-8b), a potent and selective opioid receptor-like 1 (ORL1) antagonist, was prepared and evaluated using structure-activity relationship studies with the aim of removing its affinity to human ether-a-go-go related gene (hERG) K (+) channel. From these studies, 10l was identified as an optimized structure with respect to ORL1 antagonist activity, and affinity to the hERG K (+)channel. Furthermore, 10l showed good in vivo antagonism with a wide therapeutic index in regards to adverse cardiovascular effects.
Assuntos
Cicloparafinas/química , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Antagonistas de Entorpecentes , Piridinas/administração & dosagem , Piridinas/química , Administração Oral , Animais , Fenômenos Químicos , Físico-Química , Cães , Canais de Potássio Éter-A-Go-Go/metabolismo , Hepatócitos/metabolismo , Humanos , Estrutura Molecular , Ligação Proteica , Piridinas/síntese química , Piridinas/classificação , Ratos , Receptores Opioides/metabolismo , Relação Estrutura-Atividade , Receptor de NociceptinaRESUMO
Based on reported structures, a focused library of biarylmethyl bound to the nitrogen atom of spiropiperidine was designed. Systematic modifications allowed the discovery of a synthetically feasible and highly potent ORL1 antagonist 37, 1'-{[1-(3-chloropyridin-2-yl)-1H-pyrazol-4-yl]methyl}-3H-spiro[2-benzofuran-1,4'-piperidine], which exhibits excellent selectivity to mu, kappa, and human ether-a-go-go related gene potassium channel.
