MK-8262, an orally active and potent cholesteryl ester transfer protein (CETP) inhibitor (IC 50 = 53 nM, log D = 5.3), is a bistrifluoromethyl analogue that shows promise in research related to high-density lipoprotein (HDL) and low-density lipoprotein (LDL) with potential implications for coronary heart disease (CHD).

CETP:53 nM (IC50)

MK-8262 (Compound 87) diminishes cell viability in a dose-dependent manner starting at approximately 10 μM across all eight cell lines, irrespective of human CYP expression or glutathione depletion, specifically in HEK293/CYP cell lines that express human CYP1A2, CYP2E1, CYP2D6, CYP2C8, CYP2B6, CYP3A4, CYP2C19, or CYP2C9. Furthermore, MK-8262 does not influence human CYP protein levels or Nrf2 activation in any of these cell lines.

MK-8262, administered orally at 10 mg/kg, significantly elevates HDL cholesterol levels in CETP transgenic mice following a 2-week chronic regimen[1]. When given intravenously (iv) at 1 mg/kg, MK-8262 exhibits a half-life (T 1/2 MRT) of 6 hours, a clearance (CL) rate of 2.6 mL/min/kg, and a steady-state volume of distribution (V ss) of 0.95 L/kg in mice[1]. At a 2 mg/kg oral dose (po), it achieves a maximum concentration (C max) of 0.43 μM and an area under the curve (AUC) of 7.9 μM·h[1]. A repeat of the 1 mg/kg iv dosage shows a T 1/2 MRT of 13 hours, a CL rate of 3.1 mL/min/kg, and a V ss of 2.4 L/kg[1]. Finally, a 2 mg/kg oral dosage reaches a C max of 0.4 μM and an AUC of 9.7 μM·h in mice[1].