Referenced in: none

Automatically associated channels: Kv11.1

Title: Optimization of chromone-2-carboxamide melanin concentrating hormone receptor 1 antagonists: assessment of potency, efficacy, and cardiovascular safety.

Authors: John K Lynch, Jennifer C Freeman, Andrew S Judd, Rajesh Iyengar, Mathew Mulhern, Gang Zhao, James J Napier, Dariusz Wodka, Sevan Brodjian, Brian D Dayton, Doug Falls, Christopher Ogiela, Regina M Reilly, Thomas J Campbell, James S Polakowski, Lisa Hernandez, Kennan C Marsh, Robin Shapiro, Victoria Knourek-Segel, Brian Droz, Eugene Bush, Michael Brune, Lee C Preusser, Ryan M Fryer, Glenn A Reinhart, Kathryn Houseman, Gilbert Diaz, Ann Mikhail, James T Limberis, Hing L Sham, Christine A Collins, Philip R Kym

Journal, date & volume: J. Med. Chem., 2006 Nov 2 , 49, 6569-84

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/17064075

Abstract
Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonists in an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series as having excellent safety against the chosen cardiovascular endpoints at high drug concentrations in the plasma and brain. Optimization of this series led to considerable improvements in affinity, functional potency, and pharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that was orally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat, and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascular model compared to other series reported by our group. However, this analogue also led to prolongation of the QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functional blockade of this ion channel.