SAR of biphenyl carboxamide ligands of the human melanin-concentrating hormone receptor 1 (MCH R1): Discovery of antagonist SB-568849

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.