title: Synthesis and activity of a novel series of 3-biarylquinuclidine squalene synthase inhibitors.
abstract: Quinuclidines with a 3-biaryl substituent are a new class of potent, orally active squalene synthase (SQS) inhibitors. Variants around these rigid structures indicate key structural requirements for cationic SQS inhibitors. Thus the lower in vitro potency found for quinuclidines bearing 3-substituents, which did not overlay the biphenyl group of 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (2) (IC50 = 16 nM, rat microsomal SQS), implied a directional requirement for the 3-substituent. Similarly, the lower potency of the 3-terphenyl analogue 6 (IC50 = 370 nM) indicated size constraints for this substituent. In compounds with a linking group between the quinuclidine and biphenyl ring, linking groups of lower lipophilicity were less well tolerated (e.g., 17, CH2CH2, IC50 = 5 nM vs 19, NHCO, IC50 = 1.2 microM). Replacement of the distal phenyl ring of 2 with a more polar pyridine heterocycle caused a reduction in in vitro potency. In general, good in vivo activity in the rat was restricted to 3-hydroxy analogues, with the 3-[4-(pyrid-4-yl)phenyl] derivative 39 (IC50 = 161 nM) showing the best inhibition (following oral dosing) of cholesterol biosynthesis from mevalonate (ED50 = 2.7 mg/kg).
authors.affiliation: Cardiovascular and Muscoskeletal Department, Zeneca Pharmaceuticals, Macclesfield, Cheshire, UK.
authors.forename: G R
authors.initials: GR
authors.lastname: Brown
authors.forename: D S
authors.initials: DS
authors.lastname: Clarke
authors.forename: A J
authors.initials: AJ
authors.lastname: Foubister
authors.forename: S
authors.initials: S
authors.lastname: Freeman
authors.forename: P J
authors.initials: PJ
authors.lastname: Harrison
authors.forename: M C
authors.initials: MC
authors.lastname: Johnson
authors.forename: K B
authors.initials: KB
authors.lastname: Mallion
authors.forename: J
authors.initials: J
authors.lastname: McCormick
authors.forename: F
authors.initials: F
authors.lastname: McTaggart
authors.forename: A C
authors.initials: AC
authors.lastname: Reid
authors.forename: G J
authors.initials: GJ
authors.lastname: Smith
authors.forename: M J
authors.initials: MJ
authors.lastname: Taylor
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D002784:Cholesterol / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D008798:Mevalonic Acid / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C100735:3-(4-(pyrid-4-yl)phenyl)-3-hydroxyquinuclidine; C099381:3-(biphenyl-4-yl)-3-hydroxyquinuclidine; D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D011812:Quinuclidines; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase; D008798:Mevalonic Acid