(3R,5S,E)-7-(4-(4-Fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1H-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic Acid (BMS-644950): A Rationally Designed Orally Efficacious 3-Hydroxy-3-methylglutaryl Coenzyme-A Reductase Inhibitor with Reduced Myotoxicity Potential

Abstract

3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.

Recent Progress in the Synthesis of Super-Statins

“…As a consequence, several new hepatoselective analogs of atorvastatin were derived, such as 1 [22] [29], and 8 [35]. Similarly, more hepatoselective derivatives of rosuvastatin (e.g., derivative 9) have been investigated [28,30]. Quinoline derivatives analogous to pitavastatin (e.g., derivative 10) have also been identified as interesting targets in this context [25,32,36].…”

“…The effects of multiple parameters on the progress of the asymmetric reduction were investigated to establish the optimal reaction conditions, including induction time, glucose, NADP + and substrate concentrations, temperature, and pH. This whole-cell biocatalyst preformed optimally at 28 C and pH 7, with glucose to substrate ratio of 1∶1 (w/w). Under these Scheme 11 Biocatalyzed approach to the C-7 chiral atorvastatin lateral-chain precursor using E. coli cells expressing KR and GDH for a cofactor regeneration Z. Č asar conditions, 80.0 g/L loading of t-butyl 6-cyano-(5R)-hydroxy-3-oxohexanoate 68 was fully converted to t-butyl 6-cyano-(3R,5R)-dihydroxylhexanoate 69 in 2 h, with de > 99.5%.…”

Current Developments in the Syntheses of 1,2,4-Triazole Compounds

“…Reaction of amino 1,2,4-triazole with compound 242 through deprotonation with lithium bis(trimethylsilyl)amide (LiN(TMS) 2 ) successfully afforded triazole derivative 243 in yield of 73% and then deprotection of the side chain via sequential treatment by hydrogen chloride and sodium hydroxide provided a novel potent and efficacious 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitor, which might be used in treating hypercholesterolemia and dyslipidemia with potentially excellent safety profile (Scheme 105) [307]. By the use of microwave irradiation, the one-pot reaction of salicylic aldehyde 244, 3-amino 1,2,4-triazole and acetone in ethanol at 170 °C gave triazole derivative 245 in moderate yield (47%).…”

Toxic Myopathies

“…The adverse myotoxic effects turn out to be even rarer than previously thought [15], usually minor, but easily recognizable and reversible even when serious. It is therefore safe to say that these drugs have very high safety windows [16], which make them far safer than aspirin by at least an order of magnitude but nevertheless capable of causing severe and even fatal acute necrotizing myopathy.…”