The class
Less lipophilic hexahydrofuroquinoline CETP inhibitor clears fat tissue quickly and avoids off-target hypertension signals (J Med Chem 2014)
Original title: Potent cholesteryl ester transfer protein inhibitors of reduced lipophilicity: 1,1'-spiro-substituted hexahydrofuroquinoline derivatives
Researchers identified a series of 1,1-spiro-substituted hexahydrofuroquinoline derivatives that potently inhibit cholesteryl ester transfer protein (CETP) while having reduced lipophilicity compared with earlier compounds in this class. Lead compound 26 robustly raised HDL cholesterol and lowered LDL cholesterol in transgenic hCETP/hApoB-100 mice, and, unlike highly lipophilic CETP inhibitors, was completely eliminated from fat tissue within 21 days of stopping treatment. Compound 26 showed no significant effect on aldosterone secretion from H295R cells and no significant effects on blood pressure or ECG parameters in telemetrized cynomolgus monkeys, distinguishing it from earlier CETP inhibitors linked to off-target cardiovascular safety signals.
Original abstract
A series of 1,1'-spiro-substituted hexahydrofuroquinoline derivatives exhibiting potent cholesteryl ester transfer protein (CETP) inhibition at reduced lipophilicity was identified. A focused structure-activity relationship (SAR) exploration led to the potent and comparatively polar CETP inhibitor 26 showing robust high density lipoprotein-cholesterol (HDL-C) elevation and low density lipoprotein-cholesterol (LDL-C) reduction in transgenic hCETP/hApoB-100 mice. Compound 26 was also shown to positively differentiate from highly lipophilic CETP inhibitors in its complete elimination from fat tissue in hCETP transgenic mice as evident within 21 days after cessation of treatment. In addition, compound 26 showed no significant effects on aldosterone secretion from H295R cells, as well as no significant effects on blood pressure and electrocardiogram parameters in telemetrized cynomolgus monkeys.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.