Bicyclo[3.1.0]hexyl urea melanin concentrating hormone (MCH) receptor-1 antagonists: impacting hERG liability via aryl modifications.
Herein, we report the discovery of an effective strategy to modulate liabilities related to affinity of previously disclosed bicyclohexane MCHR-1 antagonists for the hERG channel. This paper describes one of several strategies incorporated to limit hERG binding via modifications of a terminal aryl group in an otherwise promising bicyclohexyl urea series.
McBriar
Mark D
MD
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. mark.mcbriar@spcorp.com
Guzik
Henry
H
Shapiro
Sherry
S
Xu
Ruo
R
Paruchova
Jaroslava
J
Clader
John W
JW
O'neill
Kim
K
Hawes
Brian
B
Sorota
Steve
S
Margulis
Michael
M
Tucker
Kristal
K
Weston
Daniel J
DJ
Cox
Kathleen
K
D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008543:Melanins / Q000737:chemistry*; D008956:Models, Chemical; D011485:Protein Binding; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D014508:Urea / Q000737:chemistry / Q000494:pharmacology*
D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; C103263:MCHR1 protein, human; D008543:Melanins; D017481:Receptors, Somatostatin; D014508:Urea