Bicyclic[4.1.0]heptanes as phenyl replacements for melanin concentrating hormone receptor antagonists

• Published in: Bioorganic & medicinal chemistry 2006-05, Vol.14 (10), p.3285-3299
• Main Authors: Xu, Ruo, Li, Shengjian, Paruchova, Jaroslava, McBriar, Mark D., Guzik, Henry, Palani, Anandan, Clader, John W., Cox, Kathleen, Greenlee, William J., Hawes, Brian E., Kowalski, Timothy J., O’Neill, Kim, Spar, Brian D., Weig, Blair, Weston, Daniel J.
• Format: Article
• Language: English
• Subjects: Aminobiphenyl Compounds - chemistry; Animals; Bicyclo[4.1.0]heptane; Biological and medical sciences; Biphenyl amine replacement; Bridged Bicyclo Compounds - chemistry; Cell Line; Cricetinae; Drug Evaluation, Preclinical; Heptanes - chemistry; Heptanes - pharmacology; Hormones. Endocrine system; Medical sciences; Melanin concentrating hormone-1 receptor antagonist; Mice; Molecular Structure; Mutagens - chemistry; Pharmacology. Drug treatments; Rats; Receptors, Pituitary Hormone - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.12.046

Bicyclic[4.1.0]heptanes were discovered as replacements for the middle phenyl ring of the biphenylamine moiety in order to eliminate its potential mutagenic liability. Melanin concentrating hormone (MCH) receptor antagonists have been proposed as potential treatments of obesity. MCH receptor antagonists with a biphenylamine subunit have been reported previously at Schering-Plough. Herein, we report the discovery of bicyclo[4.1.0]heptanes as replacements for the middle phenyl ring of the biphenylamine moiety in order to eliminate its potential mutagenic liability. Structure–activity relationships in this series were found to be very similar to those of the original biphenylamine series, suggesting that the two series have similar binding modes.