RESUMEN
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.
Asunto(s)
Amidas/química , Amidas/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacocinética , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Bovinos , Biología Computacional , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Receptores de Somatostatina/química , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad , Azufre/químicaRESUMEN
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.