title: Quinuclidine inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase: optimization from lipid profiles.
abstract: Novel 3-substituted quinuclidine inhibitors of cholesterol biosynthesis are reported. Compounds were optimized against oxidosqualene cyclase-lanosterol synthase (OSC) inhibition in vivo, rather than by the conventional optimization of structure-activity relationship information based on in vitro OSC inhibition. Thus, examination of HPLC lipid profiles from orally dosed rats showed cholesterol biosynthetic intermediates and whether cholesterol levels were reduced. A new substituted quinuclidine pharmacophore 18a-c was rapidly found for the inhibition of OSC, and the most promising inhibitors were validated by the confirmation of potent OSC inhibition. Compound 16 gave an IC50 value of 83 +/- 11 nM for human and an IC50 value of 124 +/- 14 nM, for rat, coupled with oral and selective inhibition of cholesterol biosynthesis derived from OSC inhibition (rat, ED50 = 1.3 +/- 0.7 mg/kg, n = 5; marmoset, 15 mg/kg dose, n = 3, caused complete inhibition). These 3-substituted quinuclidines, which were derived from a quinuclidine series previously known to inhibit cholesterol biosynthesis at the squalene synthase step, may afford a novel series of hypocholesterolemic agents acting by the inhibition of OSC.
authors: Cardiovascular Metabolism & Muscoskeletal Research Department, Zeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. George.Brown@alderly.zeneca.com
authors: G R
authors: GR
authors: Brown
authors: D M
authors: DM
authors: Hollinshead
authors: E S
authors: ES
authors: Stokes
authors: D S
authors: DS
authors: Clarke
authors: M A
authors: MA
authors: Eakin
authors: A J
authors: AJ
authors: Foubister
authors: S C
authors: SC
authors: Glossop
authors: D
authors: D
authors: Griffiths
authors: M C
authors: MC
authors: Johnson
authors: F
authors: F
authors: McTaggart
authors: D J
authors: DJ
authors: Mirrlees
authors: G J
authors: GJ
authors: Smith
authors: R
authors: R
authors: Wood
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002144:Callithrix; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D050356:Lipid Metabolism; D008055:Lipids / Q000032:analysis; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D008055:Lipids; D011812:Quinuclidines; D019751:Intramolecular Transferases; C021924:lanosterol synthase