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).

Synthesis of Sulfonyl Chlorides of Phenylboronic Acids

“…Instead, complicated mixtures were formed. In contrast to these results we found that similar treatment of the corresponding N-methyldiethanolamine boronates protected esters 1 resulted in clean bromine-lithium exchange, 13 and subsequent quench with sulfur dioxide resulted in immediate precipitation of the lithium sulfinates (2a,b) which could be isolated in yields of 94% and 99%, respectively (Scheme 1). Possibly the nitrogen atom in the N-methyldiethanolamine protection group brings the boron atom in a tetrahedral and more protected state via B-N interaction, thereby making it less susceptible for attack of the butyl lithium.…”

Human isoprenoid synthase enzymes as therapeutic targets

“…Nonetheless structural optimization led to the identification of compounds with good biopharmaceutical properties, including reasonable oral bioavailability (Ishihara et al, 2004). Quinuclidine derivatives in particular, such as 33 and 34 (Brown et al, 1996), exhibited an equal or better pharmacological profile to statins in lowering cholesterol levels in hamsters, guinea pigs and Rhesus monkeys (Amin et al, 1997; Brown et al, 1997). However, none of these compounds were advanced to clinical trials; it is noteworthy that the quinuclidine structural motif is believed to be responsible for the toxicities associated with antimalarial drugs, such as quinine.…”

Design, synthesis and biological evaluation of WC-9 analogs as antiparasitic agents

“…A similar rationale has been advanced to explain the potent anti-SQS activity of arylquinuclidine derivatives against both mammalian and T.cruzi SQS [28,29]. Based on this hypothesis, it should be possible to design new and more potent SQS inhibitors, using WC-9 as lead drug.…”