Lead triphenylethanamine CETP inhibitor shows clean blood pressure profile and robust efficacy (ACS Med Chem Lett 2019)

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

ACS Med Chem Lett · 6 May 2019 · 5

Finlay HJ, Jiang J, Rampulla R, Salvati ME, Qiao JX, Wang TC, Lawrence RM, Harikrishnan LS, Kamau MG, Taylor DS, Chen AYA, Yin X et al.

Researchers describe lead optimisation of the diphenylpyridylethanamine and triphenylethanamine series of CETP inhibitors to improve pharmaceutical profile. Polar groups at the N-terminus in the diphenylpyridylethanamine series improved potency and pharmaceutical properties while retaining safety, efficacy and pharmacokinetics, and this structure-activity relationship extended to the more potent triphenylethanamine series, yielding compound 13. Compound 13 showed no significant changes in mean arterial blood pressure or heart rate in telemetry rats, had an excellent pharmacokinetic profile, and demonstrated robust efficacy in human CETP/apo-B-100 dual transgenic mice and in hamsters, indicating the blood-pressure liability seen with torcetrapib is compound-specific rather than class-wide.

Original 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.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.