RESUMO
We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability.
Assuntos
Amidas/química , Amidas/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacocinética , Animais , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Bovinos , Biologia Computacional , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Receptores de Somatostatina/química , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Enxofre/químicaRESUMO
A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.
