Bicyclo[3.1.0]hexyl urea melanin concentrating hormone (MCH) receptor-1 antagonists: impacting hERG liability via aryl modifications

Mark D McBriar; Henry Guzik; Sherry Shapiro; Ruo Xu; Jaroslava Paruchova; John W Clader; Kim O'neill; Brian Hawes; Steve Sorota; Michael Margulis; Kristal Tucker; Daniel J Weston; Kathleen Cox

doi:10.1016/j.bmcl.2006.05.069

Bicyclo[3.1.0]hexyl urea melanin concentrating hormone (MCH) receptor-1 antagonists: impacting hERG liability via aryl modifications

Bioorg Med Chem Lett. 2006 Aug 15;16(16):4262-5. doi: 10.1016/j.bmcl.2006.05.069. Epub 2006 Jun 5.

Authors

Mark D McBriar¹, Henry Guzik, Sherry Shapiro, Ruo Xu, Jaroslava Paruchova, John W Clader, Kim O'neill, Brian Hawes, Steve Sorota, Michael Margulis, Kristal Tucker, Daniel J Weston, Kathleen Cox

Affiliation

¹ Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. [email protected]

PMID: 16753297
DOI: 10.1016/j.bmcl.2006.05.069

Abstract

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.

MeSH terms

Chemistry, Pharmaceutical
Drug Design
Ether-A-Go-Go Potassium Channels / metabolism*
Humans
Inhibitory Concentration 50
Kinetics
Melanins / chemistry*
Models, Chemical
Protein Binding
Receptors, Somatostatin / antagonists & inhibitors*
Urea / chemistry
Urea / pharmacology*

Substances

Ether-A-Go-Go Potassium Channels
KCNH6 protein, human
MCHR1 protein, human
Melanins
Receptors, Somatostatin
Urea