Novel 4-piperidinopyridine inhibitors of oxidosqualene cyclase-lanosterol synthase derived by consideration of inhibitor pK(a)

G R Brown; A J Foubister; M C Johnson; N J Newcombe; D Waterson; S L Wells

doi:10.1016/s0960-894x(01)00423-1

Novel 4-piperidinopyridine inhibitors of oxidosqualene cyclase-lanosterol synthase derived by consideration of inhibitor pK(a)

Bioorg Med Chem Lett. 2001 Aug 20;11(16):2213-6. doi: 10.1016/s0960-894x(01)00423-1.

Authors

G R Brown¹, A J Foubister, M C Johnson, N J Newcombe, D Waterson, S L Wells

Affiliation

¹ AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, Cheshire, UK. george.r.brown@astrazeneca.com

PMID: 11514173
DOI: 10.1016/s0960-894x(01)00423-1

Abstract

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 pK(a) range (5.8-6.7) gave potent oral inhibition of rat cholesterol biosynthesis (8 ED(80) 0.7 mg/kg), and diminished effects on rat feeding after a 100 mg/kg oral dose.

MeSH terms

Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Intramolecular Transferases / antagonists & inhibitors*
Intramolecular Transferases / metabolism
Kinetics
Piperidines / chemical synthesis*
Piperidines / chemistry
Piperidines / pharmacology
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / pharmacology

Substances

4-piperidinopyridine
Enzyme Inhibitors
Piperidines
Pyridines
Intramolecular Transferases
lanosterol synthase