The pharmacology and off-target effects of some cholesterol ester transfer protein inhibitors.
Inhibitors of cholesterol ester transfer protein (CETP) have the capacity to increase plasma high-density lipoprotein cholesterol to unprecedented levels. Still, hopes that CETP inhibition could reduce atherosclerosis were dented when the clinical development of one such inhibitor, torcetrapib, was halted because of an unexpected finding of increased cardiovascular and noncardiovascular mortality against a background of elevated blood pressure and plasma aldosterone levels. Recently, evidence has accumulated to show that these untoward effects may have been largely attributable to off-target toxicity of the compound, unrelated to the mechanism of CETP inhibition and not shared by other CETP inhibitors. In this review, we explore the rationale for CETP inhibition, compare the pharmacology of the small molecule CETP inhibitors that reached clinical development, and address the evidence relating to off-target adverse effects.
Vergeer
Menno
M
Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam, the Netherlands.
Stroes
Erik S G
ES
D000450:Aldosterone / Q000097:blood; D000577:Amides; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D050197:Atherosclerosis / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood; D003345:Corticosterone / Q000097:blood; D004952:Esters; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000235:genetics; D023303:Oxazolidinones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000494:pharmacology
D000577:Amides; D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D004952:Esters; D023303:Oxazolidinones; D011804:Quinolines; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; D000450:Aldosterone; C483909:torcetrapib; C530884:anacetrapib; D003345:Corticosterone; D006854:Hydrocortisone