Evacetrapib

Evacetrapib is a benzazepine inhibitor of cholesteryl ester transfer protein (CETP; IC₅₀s = 5.5 and 26 nM for human recombinant and plasma-derived proteins, respectively).¹ It is selective for CETP over a panel of cell surface and nuclear receptors with no significant inhibition at 1 µM. Evacetrapib (1-10 µM) reduces expression of the serine protease proprotein convertase subtilisin kexin 9 (PCSK9) and the LDL receptor (LDLR) in HepG2 cells in a dose-dependent manner with no effect on cell viability.² It also reduces protein levels of LDLR, SREBF2-M, and PCSK9 in HepG2 lysates, nuclear extracts, and culture medium, respectively, in a dose-dependent manner. Oral administration of evacetrapib (30 mg/kg) inhibits CETP activity by 98.5, 98.6, and 18.4% after four, eight, and 24 hours, respectively, in serum from transgenic mice expressing human CETP and ApoA1.¹ Evacetrapib increases HDL cholesterol levels in CETP/ApoA1 transgenic mice in a dose-dependent manner, including by 129.7% eight hours following administration of a 30 mg/kg dose.

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1. Cao, G., Beyer, T.P., Zhang, Y., et al. Evacetrapib is a novel, potent, and selective inhibitor of cholesteryl ester transfer protein that elevates HDL cholesterol without inducing aldosterone or increasing blood pressure. J. Lipid Res. 52(12), 2169-2176 (2011).

2. Dong, B., Singh, A.B., Kan, C.F.K., et al. CETP inhibitors downregulate hepatic LDL receptor and PCSK9 expression in vitro and in vivo through a SREBP2 dependent mechanism. Atherosclerosis 235(2), 449-462 (2014).