Squalene synthase (E.C. 2.5.1.21) is a microsomal
enzyme which catalyzes the reductive dimerization of two molecules of
farnesyl diphosphate to form
squalene, and is involved in the first committed step in
cholesterol biosynthesis. It is an attractive target for hypocholesterolemic and hypotriglyceridemic strategies. We synthesized a series of 3-ethylidenequinuclidine derivatives, and evaluated their ability to inhibit
squalene synthase in vitro and to lower non-
HDL cholesterol levels in hamsters. 3-Ethylidenequinuclidine derivatives incorporating an unsubstituted
9H-carbazole moiety reduced plasma non-
HDL cholesterol levels and did not affect plasma
transaminase levels, indicating a lack of hepatotoxicity. Among the novel compounds, (Z)-2-[2-(quinuclidin-3-ylidene)ethoxy]-9H-
carbazole hydrochloride 8 (YM-53579) and (E)-2-[2-fluoro-2-(quinuclidin-3-ylidene)ethoxy]-9H-
carbazole hydrochloride 28 (YM-53601) were potent inhibitors of
squalene synthase derived from human
hepatoma cells, with IC(50) values of 160 and 79 nM, respectively. They also reduced plasma non-
HDL cholesterol levels in hamsters by approximately 50 and 70%, respectively, at an oral dose of 50 mg/kg/day for 5 days.