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Discovery of a Lead Triphenylethanamine Cholesterol Ester Transfer Protein (CETP) Inhibitor. 2019
Heather J Finlay, and
Ji Jiang, and
Richard Rampulla, and
Mark E Salvati, and
Jennifer X Qiao, and
Tammy C Wang, and
R Michael Lawrence, and
Lalgudi S Harikrishnan, and
Muthoni G Kamau, and
David S Taylor, and
Alice Ye A Chen, and
Xiaohong Yin, and
Christine S Huang, and
Ming Chang, and
Xue-Qing Chen, and
Paul G Sleph, and
Carrie Xu, and
Julia Li, and
Paul Levesque, and
Leonard P Adam, and
Ruth R Wexler
Departments of Discovery Chemistry, Biology, Preclinical Candidate Optimization, Pharmaceutics, and Bioanalytical Sciences, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
Lead optimization of the diphenylpyridylethanamine (DPPE) and triphenylethanamine (TPE) series of CETP inhibitors to improve their pharmaceutical profile is described. Polar groups at the N-terminus position in the DPPE series resulted in further improvement in potency and pharmaceutical properties concomitant with retaining the safety, efficacy, and pharmacokinetic (PK) profile. A structure-activity relationship observed in the DPPE series was extended to the corresponding analogs in the more potent TPE series, and further optimization resulted in the identification of 2-amino-N-((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanamide (13). Compound 13 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemetry rats, had an excellent PK profile, and demonstrated robust efficacy in human CETP/apo-B-100 dual transgenic mice and in hamsters.
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