Novel 4-piperidinopyridine inhibitors of oxidosqualene cyclase-lanosterol synthase derived by consideration of inhibitor pK(a).
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.
Brown
G R
GR
AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, Cheshire, UK. george.r.brown@astrazeneca.com
Foubister
A J
AJ
Johnson
M C
MC
Newcombe
N J
NJ
Waterson
D
D
Wells
S L
SL
D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C435669:4-piperidinopyridine; D004791:Enzyme Inhibitors; D010880:Piperidines; D011725:Pyridines; D019751:Intramolecular Transferases; C021924:lanosterol synthase