氨基哌啶香豆素类黑色素浓集激素受体1拮抗剂的发现与表征
Discovery and characterization of aminopiperidinecoumarin melanin concentrating hormone receptor 1 antagonists.
作者信息
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
机构信息
Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.
出版信息
J Med Chem. 2005 Sep 22;48(19):5888-91. doi: 10.1021/jm050598r.
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.
4-(1-苯并[1,3]二氧杂环戊烯-5-基甲基哌啶-4-基甲基)-6-氯色烯-2-酮（7）是一种强效的、口服生物可利用的黑色素浓缩激素受体1（MCHr1）拮抗剂，可使饮食诱导的肥胖小鼠出现剂量依赖性体重减轻。在麻醉犬心血管安全性模型中对7进行的进一步评估显示，在与最低有效治疗浓度相当的血浆浓度下会产生不良血流动力学效应。这些结果凸显了对MCHr1拮抗剂心血管安全性进行审查的必要性。
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