SYNTHESIS AND ACTIVITY OF A NOVEL SERIES OF 3-BIARYLQUINUCLIDINE SQUALENE SYNTHASE INHIBITORS

Quinuclidines with a 3-biaryl substituent are a new class of potent, o rally active squalene synthase (SQS) inhibitors. Variants around these rigid structures indicate key structural requirements for cationic SQ S 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 microsoma l SQS), implied a directional requirement for the 3-substituent. Simil arly, the lower potency of the 3-terphenyl analogue 6 (IC50 = 370 nM) indicated size constraints for this substituent. In compounds with a l inking group between the quinuclidine and biphenyl ring, linking group s of lower Lipophilicity were less well tolerated (e.g., 17, CH2CH2, I C50 = 5 nM vs 19, NHCO, IC50 = 1.2 mu M) Replacement of the distal phe nyl ring of 2 with a more polar pyridine heterocycle caused a reductio n in in vitro potency. In general, good in vivo activity in the rat wa s 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 (ED(50) = 2.7 mg/kg).