Reduction of hERG inhibitory activity in the 4-piperidinyl urea series of H3 antagonists

Michael Berlin; Yoon Joo Lee; Christopher W Boyce; Yi Wang; Robert Aslanian; Kevin D McCormick; Steve Sorota; Shirley M Williams; Robert E West Jr; Walter Korfmacher

doi:10.1016/j.bmcl.2010.01.121

Reduction of hERG inhibitory activity in the 4-piperidinyl urea series of H3 antagonists

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2359-64. doi: 10.1016/j.bmcl.2010.01.121. Epub 2010 Jan 28.

Authors

Michael Berlin¹, Yoon Joo Lee, Christopher W Boyce, Yi Wang, Robert Aslanian, Kevin D McCormick, Steve Sorota, Shirley M Williams, Robert E West Jr, Walter Korfmacher

Affiliation

¹ Chemical Research, Cardiovascular/Metabolic Diseases and CNS Discovery, and Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Kenilworth, NJ 07033, USA. michael.berlin@merck.com

PMID: 20188550
DOI: 10.1016/j.bmcl.2010.01.121

Abstract

Structural features of the substituted 4-piperidinyl urea analogs 1, responsible for the H3 antagonist activity, have been identified. Structure-activity relationship of the H3 receptor affinity, hERG ion channel inhibitory activity and their separation is described. Preliminary pharmacokinetic evaluation of the compounds of the series is addressed.

MeSH terms

Animals
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
Ether-A-Go-Go Potassium Channels / metabolism
Histamine Antagonists / chemistry
Histamine Antagonists / pharmacokinetics
Histamine Antagonists / pharmacology*
Humans
Piperidines / chemistry
Piperidines / pharmacokinetics
Piperidines / pharmacology*
Rats
Receptors, Histamine H3 / metabolism*
Structure-Activity Relationship
Urea / chemistry
Urea / pharmacokinetics
Urea / pharmacology*

Substances

Ether-A-Go-Go Potassium Channels
Histamine Antagonists
Piperidines
Receptors, Histamine H3
Urea