RESUMO
Optimization of the lead 2a led to the identification of a novel diarylketoxime class of melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. Our focus was directed toward improvement of hERG activity and metabolic stability. The representative derivative 4b showed potent and dose-dependent body weight reduction in diet-induced obese (DIO) C57BL/6J mice after oral administration. The synthesis and structure-activity relationships of the novel diarylketoxime MCH-1R antagonists are described.
Assuntos
Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Canais de Potássio Éter-A-Go-Go/metabolismo , Obesidade/tratamento farmacológico , Oximas/química , Oximas/uso terapêutico , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Peso Corporal/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Oximas/farmacocinética , Oximas/farmacologia , Ligação Proteica , Receptores de Somatostatina/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of cyclohexanamine derivatives was designed and synthesized as potent and selective human neuropeptide Y Y1 receptor antagonists. Modification of high-throughput screening hit compound 1 resulted in the identification of compound 3i, which displays potent Y1 activity and good selectivity towards hERG K(+) channel and serotonin transporter.
Assuntos
Cicloexilaminas/química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Linhagem Celular , Cicloexilaminas/síntese química , Cicloexilaminas/farmacologia , Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Receptores de Neuropeptídeo Y/metabolismo , Serotonina/metabolismo , Relação Estrutura-AtividadeRESUMO
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
The synthesis and biological evaluation of new potent opioid receptor-like 1 (ORL1) antagonists are presented. Conversion of the thioether linkage of the prototype [It is reported prior to this communication as a consecutive series.: Kobayashi, K.; Kato, T.; Yamamoto, I.; Shimizu, A.; Mizutani, S.; Asai, M.; Kawamoto, H.; Ito, S.; Yoshizumi, T.; Hirayama, M.; Ozaki, S.; Ohta, H.; Okamoto, O. Bioorg. Med. Chem. Lett., in press] to the carbonyl linker effectively reduces susceptibility to P-glycoprotein (P-gp) efflux. This finding led to the identification of 2-cyclohexylcarbonylbenzimizole analogue 7c, which exhibited potent ORL1 activity, excellent selectivity over other receptors and ion channels, and poor susceptibility to P-gp. Compound 7c also showed satisfactory pharmacokinetic profiles and brain penetrability in laboratory animals. Furthermore, 7c showed good in vivo antagonism. Hence, 7c was selected as a clinical candidate for a brain-penetrable ORL1 antagonist.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacocinética , Cicloexanos/química , Cicloexanos/farmacocinética , Antagonistas de Entorpecentes , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Animais , Benzimidazóis/síntese química , Encéfalo/metabolismo , Linhagem Celular , Cicloexanos/síntese química , Cães , Haplorrinos , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Ratos , Receptores Opioides/metabolismo , 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.
Assuntos
Química Farmacêutica/métodos , Antagonistas de Entorpecentes , Piperidinas/química , Compostos de Espiro/química , Ligação Competitiva , Desenho de Fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Ligação Proteica , Receptores Opioides , 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.