RESUMO
A novel series of [6-chloro-2-trifluoromethyl-7-aryl-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-dialkylamines was discovered as potent CRF(1)R antagonists. The optimization of binding affinity in the series by the parallel reaction approach is discussed herein.
Assuntos
Imidazóis/química , Metilaminas/química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Humanos , Imidazóis/farmacologia , Metilaminas/farmacologia , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
7-Aryl-6,7-dihydroimidazoimidazoles represent a novel series of high-affinity corticotropin-releasing factor 1 receptor antagonists. Here, we report their synthesis and SAR as well as behavioral activity of two exemplary compounds, 7b and 7k, in a mouse canopy model of anxiety.
Assuntos
Ansiolíticos/síntese química , Imidazóis/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Barreira Hematoencefálica , Hormônio Liberador da Corticotropina , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Camundongos , Ratos , Relação Estrutura-AtividadeRESUMO
[structures: see text] A stereocontrolled racemic synthesis of conformationally restricted analogues 2a and 2b of a potent CGRP receptor antagonist 1 by novel functionalization of 2-substituted octahydropyrido[1,2-a]pyrazin-6-ones is described. The new diastereoselective LDA-promoted alpha-nitration of intermediate lactams established the required trans-configuration in the desired products.
Assuntos
Benzimidazóis/síntese química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Piperazinas/síntese química , Piperidinas/síntese química , Pirazinas/química , Benzimidazóis/química , Cristalografia por Raios X , Lactamas/química , Conformação Molecular , Estrutura Molecular , Piperazinas/química , Piperidinas/química , EstereoisomerismoRESUMO
An efficient approach was developed to synthesize 2-(2,4,6-trichlorophenylamino)-4-trifluoromethyl-5-aminomethylthiazoles, corticotropin-releasing factor type 1 receptor (CRF(1)R) antagonists, by monoalkylation of amines with chloromethyl intermediate 5. The effect of variations in aminomethyl side chain of 6 on binding affinity is discussed.
Assuntos
Hidrocarbonetos Halogenados/síntese química , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Sítios de Ligação , Hidrocarbonetos Halogenados/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologiaRESUMO
Collections of small secondary amines for compound library generation can be efficiently prepared by amide reduction using BH(3)-THF or Red-Al followed by brief methanolysis, trapping with di-tert-butyl dicarbonate, and deprotection with 4M HCl in dioxane. The sequence requires no chromatography or distillation and provides multi-gram quantities of pure HCl salts in a short time.
Assuntos
Aminas/síntese química , Química Farmacêutica/métodos , Biblioteca de Peptídeos , Sais/síntese química , Aminas/análise , Cromatografia Gasosa/métodos , Técnicas de Química Combinatória/métodos , Sais/análiseRESUMO
2-arylamino-4-trifluoromethyl-5-aminomethylthiazoles represent a novel series of high-affinity corticotropin releasing factor-1 receptor (CRF(1)R) antagonists that are prepared in three steps in good overall yields. Herein, we report binding SAR as well as anxiolytic activity of an exemplary compound (7a, K(i)=8.6 nM) in a mouse canopy model.