Lead optimization of melanin concentrating hormone receptor 1 antagonists with low hERG channel activity.
The discovery of small molecule melanin concentrating hormone receptor (MHCr1) antagonists as novel therapeutic agents has been widely pursued across the pharmaceutical industry. While multiple chemotypes of small molecule MCHr1 antagonists have been identified and shown to induce weight loss in rodent models of obesity, many of these lead compounds have been found to cross react with the hERG channel. This review describes efforts that led to the identification of two sub-series of MCHr1 antagonists with low affinity for the hERG channel. Ultimately, however, the modifications introduced to thwart hERG channel activity resulted in lead compounds with sub-optimal CNS behavior.
Judd
Andrew S
AS
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. andrew.judd@abbott.com
Souers
Andrew J
AJ
Kym
Philip R
PR
D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism
D051638:Ether-A-Go-Go Potassium Channels; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor