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.
Witty
David R
DR
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. david.witty@gsk.com
Bateson
John H
JH
Hervieu
Guillaume J
GJ
Jeffrey
Phillip
P
Johnson
Christopher N
CN
Muir
Alison I
AI
O'Hanlon
Peter J
PJ
Stemp
Geoffrey
G
Stevens
Alex J
AJ
Thewlis
Kevin M
KM
Wilson
Shelagh
S
Winborn
Kim Y
KY
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D019295:Computational Biology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013455:Sulfur / Q000737:chemistry
D000577:Amides; D001713:Biphenyl Compounds; D008024:Ligands; C103263:MCHR1 protein, human; D017481:Receptors, Somatostatin; C514078:SB-568849; D013455:Sulfur