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 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.
Brown
G R
GR
AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K. George.R.Brown@astrazeneca.com
Hollinshead
D M
DM
Stokes
E S
ES
Waterson
D
D
Clarke
D S
DS
Foubister
A J
AJ
Glossop
S C
SC
McTaggart
F
F
Mirrlees
D J
DJ
Smith
G J
GJ
Wood
R
R
D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002784:Cholesterol / Q000096:biosynthesis; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
C419155:1-(2-methyl-4-pyrimidinyl)-4-(1-(4-bromophenylsulfonyl)piperazin-4-ylcarbonyl)piperidine; C419154:1-(4-pyrimidinyl)-4-(1-(4-bromophenylsulfonyl)piperazin-4-ylcarbonyl)piperidine; D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D011743:Pyrimidines; D002784:Cholesterol; D019751:Intramolecular Transferases; C021924:lanosterol synthase