Diphenylpyridylethanamine (DPPE) Derivatives as Cholesteryl Ester Transfer Protein (CETP) Inhibitors

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• 作者：Lalgudi S. Harikrishnan ; Heather J. Finlay ; Jennifer X. Qiao ; Muthoni G. Kamau ; Ji Jiang ; Tammy C. Wang ; James Li ; Christopher B. Cooper ; Michael A. Poss ; Leonard P. Adam ; David S. Taylor ; Alice Ye A. Chen ; Xiaohong Yin ; Paul G. Sleph ; Richard Z. Yang ; Doree F. Sitkoff ; Michael A. Galella ; David S. Nirschl ; Katy Van Kirk ; Arthur V. Miller ; Christine S. Huang ; Ming Chang ; Xue-Qing Chen ; Mark E. Salvati ; Ruth R. Wexler ; R. Michael Lawrence
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：July 12, 2012
• 年：2012
• 卷：55
• 期：13
• 页码：6162-6175
• 全文大小：446K
• 年卷期：v.55,no.13(July 12, 2012)
• ISSN：1520-4804

文摘

A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.