| Literature DB >> 22650305 |
Lalgudi S Harikrishnan1, 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.
Abstract
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.Entities:
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Year: 2012 PMID： 22650305 DOI： 10.1021/jm300611v
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446