Quinuclidine inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase: Optimization from lipid profiles

Novel 3-substituted quinuclidine inhibitors of cholesterol biosynthesis are reported. Compounds were optimized against oxidosqualene cyclase-lanostero l synthase (OSC) inhibition in vivo, rather than by the conventional optimi zation of structure-activity relationship information based on in vitro OSC inhibition. Thus; examination of HPLC lipid profiles from orally dosed rat s showed cholesterol biosynthetic intermediates and whether cholesterol lev els were reduced. A new substituted quinuclidine pharmacophore 18a-c was ra pidly found for the inhibition of OSC, and the most promising inhibitors we re validated by the confirmation of potent OSC inhibition. Compound 16 gave an IC50 value of 83 +/- 11 nM for human and an IC50 value of 124 +/- 14 nM , for rat, coupled with oral and selective inhibition of cholesterol biosyn thesis derived from OSC inhibition (rat, ED50 = 1.3 +/- 0.7 mg/kg, n = 5; m armoset, 15 mg/kg dose, it = 3, caused complete inhibition). These 3-substi tuted quinuclidines, which were derived from a quinuclidine series previous ly known to inhibit cholesterol biosynthesis at the squalene synthase step, may afford a novel series of hypocholesterolemic agents acting by the inhi bition of OSC.