A novel series of 4-piperidinopyridine and 4-piperidinopyrimidine inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase

A novel series of 4-piperidinopyridines and 4-piperidinopyrimidines showed potent and selective inhibition of rat 2,3-oxidosqualene cyclase-lanosterol synthase (OSC) (e.g. 26 IC50 rat = 398 +/- 25 nM, human = 112 +/- 25 nM) a nd gave selective oral inhibition of rat cholesterol biosynthesis (26 ED80 = 1.2 +/- 0.3 mg/kg, n = 5; HMGCoA reductase inhibitor simvastatin, ED80 = 1.2 +/- 0.3 mg/kg, n = 5). The piperidinopyrimidine OSC inhibitors have a s ignificantly lower pK(a) than the corresponding pyridine or the previously reported quinuclidine OSC inhibitor series. This indicates that other novel OSC inhibitors may be found in analogues of this series across a broader p K(a) range (6.0-9.0). These series may yield novel hypocholesterolemic agen ts for the treatment of cardiovascular disease.