title: Novel 4-piperidinopyridine inhibitors of oxidosqualene cyclase-lanosterol synthase derived by consideration of inhibitor pK(a).
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.
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, Cheshire, UK. george.r.brown@astrazeneca.com
authors.forename: G R
authors.initials: GR
authors.lastname: Brown
authors.forename: A J
authors.initials: AJ
authors.lastname: Foubister
authors.forename: M C
authors.initials: MC
authors.lastname: Johnson
authors.forename: N J
authors.initials: NJ
authors.lastname: Newcombe
authors.forename: D
authors.initials: D
authors.lastname: Waterson
authors.forename: S L
authors.initials: SL
authors.lastname: Wells
mesh_terms: 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
chemical_list: C435669:4-piperidinopyridine; D004791:Enzyme Inhibitors; D010880:Piperidines; D011725:Pyridines; D019751:Intramolecular Transferases; C021924:lanosterol synthase