Discovery and Characterization of Aminopiperidinecoumarin Melanin Concentrating Hormone Receptor 1 Antagonists

4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evaluation of 7 in an anesthetized dog model of car...

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Veröffentlicht in:	Journal of medicinal chemistry 2005-09, Vol.48 (19), p.5888-5891
Hauptverfasser:	Kym, Philip R, Iyengar, Rajesh, Souers, Andrew J, Lynch, John K, Judd, Andrew S, Gao, Ju, Freeman, Jennifer, Mulhern, Mathew, Zhao, Gang, Vasudevan, Anil, Wodka, Dariusz, Blackburn, Christopher, Brown, Jim, Che, Jennifer Lee, Cullis, Courtney, Lai, Su Jen, LaMarche, Matthew J, Marsilje, Tom, Roses, Jon, Sells, Todd, Geddes, Brad, Govek, Elizabeth, Patane, Michael, Fry, Dennis, Dayton, Brian D, Brodjian, Sevan, Falls, Doug, Brune, Michael, Bush, Eugene, Shapiro, Robin, Knourek-Segel, Victoria, Fey, Thomas, McDowell, Cathleen, Reinhart, Glenn A, Preusser, Lee C, Marsh, Kennan, Hernandez, Lisa, Sham, Hing L, Collins, Christine A
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Anti-Obesity Agents - adverse effects Anti-Obesity Agents - chemical synthesis Anti-Obesity Agents - pharmacology Biological and medical sciences Biological Availability Blood Pressure - drug effects Brain - metabolism Cell Line, Tumor Coumarins - adverse effects Coumarins - chemical synthesis Coumarins - pharmacology Dogs Eating - drug effects Energy Metabolism General and cellular metabolism. Vitamins Humans Male Medical sciences Mice Mice, Obese Myocardial Contraction - drug effects Pharmacology. Drug treatments Piperidines - adverse effects Piperidines - chemical synthesis Piperidines - pharmacology Radioligand Assay Receptors, Pituitary Hormone - antagonists & inhibitors Receptors, Somatostatin - antagonists & inhibitors Structure-Activity Relationship
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Zusammenfassung:	4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evaluation of 7 in an anesthetized dog model of cardiovascular safety revealed adverse hemodynamic effects at a plasma concentration comparable to the minimally effective therapeutic concentration. These results highlight the need for scrutiny of the cardiovascular safety profile of MCHr1 antagonists.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm050598r