Novel 4-piperidinopyridine inhibitors of oxidosqualene cyclase-lanosterol synthase derived by consideration of inhibitor pKa

Potent inhibition of rat microsomal oxidosqualene cyclase-lanosterol synthase (OSC) was maintained after structural modification of the 4-piperidinopyridine OSC inhibitor series. These novel analogues with a much lower pKa range (5.8–6.7) gave potent oral inhibition of rat cholesterol biosynthesis (8 ED80 0.7 mg/kg), and diminished effects on rat feeding after a 100 mg/kg oral dose.