Discovery of a Lead Triphenylethanamine Cholesterol Ester Transfer Protein (CETP) Inhibitor

  • ACS Med Chem Lett. 2019 May 6;10(6):911-916. doi: 10.1021/acsmedchemlett.9b00086.
Heather J Finlay  1 ,  Ji Jiang  1 ,  Richard Rampulla  1 ,  Mark E Salvati  1 ,  Jennifer X Qiao  1 ,  Tammy C Wang  1 ,  R Michael Lawrence  1 ,  Lalgudi S Harikrishnan  1 ,  Muthoni G Kamau  1 ,  David S Taylor  1 ,  Alice Ye A Chen  1 ,  Xiaohong Yin  1 ,  Christine S Huang  1 ,  Ming Chang  1 ,  Xue-Qing Chen  1 ,  Paul G Sleph  1 ,  Carrie Xu  1 ,  Julia Li  1 ,  Paul Levesque  1 ,  Leonard P Adam  1 ,  Ruth R Wexler  1
Affiliations
  • 1. 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.
PMID: 31223447 DOI: 10.1021/acsmedchemlett.9b00086
Abstract

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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