A Novel Series of 4-Piperidinopyridine and 4-Piperidinopyrimidine Inhibitors of 2,3-Oxidosqualene Cyclase−Lanosterol Synthase

Abstract

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 IC(50) rat = 398 +/- 25 nM, human = 112 +/- 25 nM) and gave selective oral inhibition of rat cholesterol biosynthesis (26 ED(80) = 1.2 +/- 0.3 mg/kg, n = 5; HMGCoA reductase inhibitor simvastatin ED(80) = 1.2 +/- 0.3 mg/kg, n = 5). The piperidinopyrimidine OSC inhibitors have a significantly 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 pK(a) range (6.0-9.0). These series may yield novel hypocholesterolemic agents for the treatment of cardiovascular disease.

Industrial scale high-throughput screening delivers multiple fast acting macrofilaricides

“…The 9 hit series identified in this campaign are not only new anti- Wolbachia chemotypes, but also novel antibacterial chemotypes. The only series to appear in the literature is Cluster 1; 4-piperidino pyrimidines, which are selective inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase in the cholesterol biosynthesis pathway 32 . Intriguingly Wolbachia are known to perturb cholesterol homoeostasis in infected host cells 33 .…”

Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels

“…1-((Benzyloxy)carbonyl)piperidine-4-carboxylic Acid (6c). 47 The title compound was isolated as a white solid in 95% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 10.72 (s, 1H), 7.39−7.29 (m, 5H), 5.13 (s, 2H), 4.10 (s, 2H), 2.95 (s, 2H), 2.51 (tt, J = 10.7, 3.8 Hz, 1H), 1.93 (s, 2H), 1.67 (d, J = 10.3 Hz, 2H).…”

Practical Synthesis of α‐Amyrin, β‐Amyrin, and Lupeol: The Potential Natural Inhibitors of Human Oxidosqualene Cyclase

“…Different from plant OSCs, human OSC converts (3 S )‐2,3‐oxidosqualene into lanosterol, and thus plays a decisive role in cholesterol biosynthesis and homeostasis whose disorders are correlated with a variety of metabolic diseases . Notably, inhibition of human OSC has been regarded as a potential therapeutic approach to hypercholesterolemia (Fig. and Supporting Information Fig.…”