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

G R Brown; D M Hollinshead; E S Stokes; D Waterson; D S Clarke; A J Foubister; S C Glossop; F McTaggart; D J Mirrlees; G J Smith; R Wood

doi:10.1021/jm000139k

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

J Med Chem. 2000 Dec 28;43(26):4964-72. doi: 10.1021/jm000139k.

Authors

G R Brown¹, D M Hollinshead, E S Stokes, D Waterson, D S Clarke, A J Foubister, S C Glossop, F McTaggart, D J Mirrlees, G J Smith, R Wood

Affiliation

¹ AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K. [email protected]

PMID: 11150166
DOI: 10.1021/jm000139k

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.

MeSH terms

Administration, Oral
Animals
Anticholesteremic Agents / chemical synthesis*
Anticholesteremic Agents / chemistry
Anticholesteremic Agents / pharmacology
Cholesterol / biosynthesis
Chromatography, High Pressure Liquid
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Female
In Vitro Techniques
Intramolecular Transferases / antagonists & inhibitors*
Microsomes / drug effects
Microsomes / enzymology
Piperazines / chemical synthesis*
Piperazines / chemistry
Piperazines / pharmacology
Piperidines / chemical synthesis*
Piperidines / chemistry
Piperidines / pharmacology
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / pharmacology
Pyrimidines / chemical synthesis*
Pyrimidines / chemistry
Pyrimidines / pharmacology
Rats
Structure-Activity Relationship

Substances

1-(2-methyl-4-pyrimidinyl)-4-(1-(4-bromophenylsulfonyl)piperazin-4-ylcarbonyl)piperidine
1-(4-pyrimidinyl)-4-(1-(4-bromophenylsulfonyl)piperazin-4-ylcarbonyl)piperidine
Anticholesteremic Agents
Enzyme Inhibitors
Piperazines
Piperidines
Pyridines
Pyrimidines
Cholesterol
Intramolecular Transferases
lanosterol synthase