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

  • Bioorg Med Chem Lett. 2006 Sep 15;16(18):4865-71. doi: 10.1016/j.bmcl.2006.06.056.
David R Witty  1 ,  John H Bateson ,  Guillaume J Hervieu ,  Phillip Jeffrey ,  Christopher N Johnson ,  Alison I Muir ,  Peter J O'Hanlon ,  Geoffrey Stemp ,  Alex J Stevens ,  Kevin M Thewlis ,  Shelagh Wilson ,  Kim Y Winborn
Affiliations
  • 1. GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. [email protected]
PMID: 16839761 DOI: 10.1016/j.bmcl.2006.06.056
Abstract

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.

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