Screening for Cardiovascular Safety:  A Structure−Activity Approach for Guiding Lead Selection of Melanin Concentrating Hormone Receptor 1 Antagonists

• Published in: Journal of medicinal chemistry Vol. 49; no. 7; pp. 2339 - 2352
• Main Authors: Kym, Philip R, Souers, Andrew J, Campbell, Thomas J, Lynch, John K, Judd, Andrew S, Iyengar, Rajesh, Vasudevan, Anil, Gao, Ju, Freeman, Jennifer C, Wodka, Dariusz, Mulhern, Mathew, Zhao, Gang, Wagaw, Seble H, Napier, James J, Brodjian, Sevan, Dayton, Brian D, Reilly, Regina M, Segreti, Jason A, Fryer, Ryan M, Preusser, Lee C, Reinhart, Glenn A, Hernandez, Lisa, Marsh, Kennan C, Sham, Hing L, Collins, Christine A, Polakowski, James S
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 06-04-2006
• Subjects: Animals; Anti-Obesity Agents - adverse effects; Anti-Obesity Agents - blood; Anti-Obesity Agents - chemical synthesis; Biological and medical sciences; Blood Pressure - drug effects; Brain - metabolism; Cardiovascular System - drug effects; Cell Line, Tumor; Chromones - adverse effects; Chromones - blood; Chromones - chemical synthesis; Dogs; Hormones. Endocrine system; Indazoles - adverse effects; Indazoles - blood; Indazoles - chemical synthesis; Male; Medical sciences; Mice; Mice, Inbred C57BL; Myocardial Contraction - drug effects; Pharmacology. Drug treatments; Piperidines - adverse effects; Piperidines - blood; Piperidines - chemical synthesis; Rats; Rats, Sprague-Dawley; Receptors, Somatostatin - antagonists & inhibitors; Structure-Activity Relationship; Tissue Distribution; Fissipedia; Carnivora; Intravenous administration; Toxicity; Cardiovascular disease; In vitro; Indazole derivatives; Screening; In vivo; Vertebrata; Mammalia; Structure activity relation; Animal; Melanin concentrating hormone; Piperidine derivatives; Antagonist; Safety; Chemical synthesis; Dog; Biological receptor; Hormonal receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0512286

An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor 1 (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (>40 μM) and brain (>20 μg/g) with <15% change in cardiovascular endpoints. As a result of these stringent requirements, lead optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHr1 antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.