Screening for Cardiovascular Safety: a Structure-activity Approach for Guiding Lead Selection of Melanin Concentrating Hormone Receptor 1 Antagonists.
From: Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. phil.kym@abbott.com
Journal of medicinal chemistry
- Publish Date: Apr 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 7
- Pages: 2339-52
- Medium: Print
- Language: English
- Citation (JAMA): Kym Philip R, Souers Andrew J, Campbell Thomas J, et al. Screening for Cardiovascular Safety: a Structure-activity Approach for Guiding Lead Selection of Melanin Concentrating Hormone Receptor 1 Antagonists.. J. Med. Chem. Apr 2006;49:2339-52
Abstract
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 microM) and brain (>20 microg/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.
Mesh Headings (Keywords): Animals, Anti-Obesity Agents, Blood Pressure, Brain, Cardiovascular System, Cell Line, Tumor, Chromones, Dogs, Indazoles, Male, Mice, Mice, Inbred C57BL, Myocardial Contraction, Piperidines, Rats, Rats, Sprague-Dawley, Receptors, Somatostatin, Structure-Activity Relationship, Tissue Distribution
Check for Full Text / PubMed Unique Identifier (PMID): 16570930
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