Optimization of piperidin-4-yl-urea-containing melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Reducing hERG-associated liabilities

Susanne Berglund; Bryan J Egner; Henrik Gradén; Joakim Gradén; David G A Morgan; Tord Inghardt; Fabrizio Giordanetto

doi:10.1016/j.bmcl.2009.05.066

Optimization of piperidin-4-yl-urea-containing melanin-concentrating hormone receptor 1 (MCH-R1) antagonists: Reducing hERG-associated liabilities

Bioorg Med Chem Lett. 2009 Aug 1;19(15):4274-9. doi: 10.1016/j.bmcl.2009.05.066. Epub 2009 May 27.

Authors

Susanne Berglund¹, Bryan J Egner, Henrik Gradén, Joakim Gradén, David G A Morgan, Tord Inghardt, Fabrizio Giordanetto

Affiliation

¹ Medicinal Chemistry, AstraZeneca R&D Mölndal, Pepparedsleden 1, SE-431 83, Mölndal, Sweden.

PMID: 19500982
DOI: 10.1016/j.bmcl.2009.05.066

Abstract

The discovery and optimization of piperidin-4-yl-urea derivatives as MCH-R1 antagonists is herein described. Previous work around the piperidin-4-yl-amides led to the discovery of potent MCH-R1 antagonists. However, high affinity towards the hERG potassium channel proved to be an issue. Different strategies to increase hERG selectivity were implemented and resulted in the identification of piperidin-4-yl-urea compounds as potent MCH-R1 antagonists with minimized hERG inhibition.

MeSH terms

Animal Feed
Animals
Cell Line
Chemistry, Pharmaceutical / methods*
Drug Design
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
Feeding Behavior
Humans
Inhibitory Concentration 50
Models, Chemical
Obesity / drug therapy
Piperidines / chemistry*
Protein Binding
Rats
Receptors, Pituitary Hormone / antagonists & inhibitors*
Urea / analogs & derivatives*
Urea / chemistry*

Substances

ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
KCNH2 protein, human
Piperidines
Receptors, Pituitary Hormone
melanin-concentrating hormone receptor
Urea