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.
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