Discovery of a Lead Triphenylethanamine Cholesterol Ester Transfer Protein (CETP) Inhibitor.
Basic Information
ID: ALA4364272
Journal: ACS Med Chem Lett
Title: Discovery of a Lead Triphenylethanamine Cholesterol Ester Transfer Protein (CETP) Inhibitor.
Authors: Finlay HJ, Jiang J, Rampulla R, Salvati ME, Qiao JX, Wang TC, Lawrence RM, Harikrishnan LS, Kamau MG, Taylor DS, Chen AYA, Yin X, Huang CS, Chang M, Chen XQ, Sleph PG, Xu C, Li J, Levesque P, Adam LP, Wexler RR.
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.
CiteXplore: 31223447
DOI: 10.1021/acsmedchemlett.9b00086
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