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Diphenylpyridylethanamine (DPPE) derivatives as cholesteryl ester transfer protein (CETP) inhibitors. 2012
Lalgudi S Harikrishnan, and
Heather J Finlay, and
Jennifer X Qiao, and
Muthoni G Kamau, and
Ji Jiang, and
Tammy C Wang, and
James Li, and
Christopher B Cooper, and
Michael A Poss, and
Leonard P Adam, and
David S Taylor, and
Alice Ye A Chen, and
Xiaohong Yin, and
Paul G Sleph, and
Richard Z Yang, and
Doree F Sitkoff, and
Michael A Galella, and
David S Nirschl, and
Katy Van Kirk, and
Arthur V Miller, and
Christine S Huang, and
Ming Chang, and
Xue-Qing Chen, and
Mark E Salvati, and
Ruth R Wexler, and
R Michael Lawrence
Department of Chemistry, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. Lalgudi.Harikrishnan@bms.com
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.
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