RESUMEN
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.
Asunto(s)
Ciclopentanos/química , Antagonistas de Narcóticos , Pirazoles/química , Ciclopentanos/síntesis química , Ciclopentanos/farmacología , Descubrimiento de Drogas , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Pirazoles/síntesis química , Pirazoles/farmacología , Receptores Opioides/metabolismo , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
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.
Asunto(s)
Encéfalo/metabolismo , Antagonistas de Narcóticos , Nitrilos/química , Pirazoles/química , Administración Oral , Animales , Humanos , Ratones , Nitrilos/administración & dosificación , Nitrilos/farmacocinética , Pirazoles/administración & dosificación , Pirazoles/farmacocinética , Ratas , Receptores Opioides/metabolismo , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
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.
Asunto(s)
4-Aminopiridina/análogos & derivados , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Receptores de Neuropéptido Y/antagonistas & inhibidores , 4-Aminopiridina/química , Animales , Células CHO , Línea Celular , Química Farmacéutica/métodos , Cricetinae , Cricetulus , Diseño de Fármacos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/química , Humanos , Concentración de Iones de Hidrógeno , Concentración 50 Inhibidora , Modelos Químicos , Receptores de Neuropéptido Y/química , Proteínas Recombinantes/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Química Farmacéutica/métodos , Antagonistas de Narcóticos , Piperidinas/química , Compuestos de Espiro/química , Unión Competitiva , Diseño de Fármacos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Estructura Molecular , Unión Proteica , Receptores Opioides , Relación Estructura-Actividad , Receptor de NociceptinaRESUMEN
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.