Quinuclidine inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase: optimization from lipid profiles.
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.
Brown
G R
GR
Cardiovascular Metabolism & Muscoskeletal Research Department, Zeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. George.Brown@alderly.zeneca.com
Hollinshead
D M
DM
Stokes
E S
ES
Clarke
D S
DS
Eakin
M A
MA
Foubister
A J
AJ
Glossop
S C
SC
Griffiths
D
D
Johnson
M C
MC
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; 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
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D008055:Lipids; D011812:Quinuclidines; D019751:Intramolecular Transferases; C021924:lanosterol synthase