Squalene Synthase Inhibitors: An Update on the Search for New Antihyperlipidemic and Antiatherosclerotic Agents

Abstract

Atherosclerosis and related heart disease is strongly associated with elevated blood levels of total (and LDL) cholesterol. Due to the widespread incidence as well as severity of this pathological condition, major efforts have been made for the discovery and development of hypocholesteroleamic agents. In the past few decades, HMG-CoA reductase inhibitors (statins) are being extensively used as lipid lowering drugs. These agents act predominantly by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) that is the rate limiting step of cholesterol biosynthesis. Both the success as well as drawbacks of HMGRIs, have led to the investigation and design of inhibitors of other (downstream) enzymes involved in the multistep cholesterol biosynthetic pathway. One such class of agents consists of the squalene sythase inhibitors which act at the first and solely committed step towards the biosynthesis of the cholesterol nucleus. This target is considered not to interfere with the biosynthesis of other biologically important molecules and thus a better side-effect profile is expected for these inhibitors. Several classes of squalene synthase inhibitors (SQSIs), such as substrate or transition-state analogues, zaragozic acids or 2,8- dioxabicyclo[3.2.1]octane derivatives, dicarboxylic acid and quinuclidine derivatives, 4,1-benzoxazepine as well as substituted morpholine derivatives, have been studied as potent inhibitors of squalene synthase. So far only one benzoxazepine derivative (TAK-475) has been evaluated in advanced clinical trials. In this article we review the up to date research and literature on the therapeutic potential of this relatively new class of compounds, the drug discovery efforts towards the development of active squalene synthase inhibitors, their activity profile and effectiveness, as well as their structure-activity relationships.

Structural and Functional Analysis of Bacillus subtilis YisP Reveals a Role of Its Product in Biofilm Production

“…(Oldfield, 2010; Oldfield and Lin, 2012) One such class of molecules catalyze the “head-to-head” condensation of isoprenoid diphosphates to form tri- terpenes such as squalene and dehydrosqualene, reactions catalyzed by squalene synthase (SQS) and dehydrosqualene synthase (CrtM, in Staphylococcus aureus ), respectively (Figure 1). Inhibition of squalene synthase is of interest in the context of the development of cholesterol-lowering drugs (Kourounakis, et al, 2011), and of antiparasitics targeting ergosterol biosynthesis (Shang, et al, 2014; Urbina, 2009), while CrtM is of interest since in S. aureus , it is involved in formation of staphyloxanthin (Pelz, et al, 2005; Wieland, et al, 1994), a virulence factor for the organism providing resistance to killing from host reactive oxygen species. (Clauditz, et al, 2006; Liu, et al, 2005) Interestingly, staphyloxanthin levels are elevated in S. aureus biofilms (Resch, et al, 2005), and the CrtM inhibitor zaragozic acid (Figure 1B) inhibits biofilm formation by affecting lipid micro-domain (“raft”) organization.…”

Enzymatic Targets in Atherosclerosis

“…Thus, it was expected that SQS pharmacological targeting would be an attractive approach for the treatment of atherosclerosis due to reduced side effects. To this aim, various SQS inhibitors were assessed for their capacity of lowering cholesterol level [19]. Among these, the benzoxazepine derivative lapaquistat acetate (TAK-475) seemed the most promising.…”

“…For an extensive review of SQS inhibitors as antiatherosclerotic agents, the reader is directed to the recent comprehensive review of Kourounakis [19].…”

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

“…Inhibitors of squalene synthase have sparked interest as selective cholesterol lowering agents [76–77]. The enzyme is involved in the first committed step in the cholesterol synthesis and catalyses the conversion of two molecules of farnesyl diphosphate into squalene, which is later converted exclusively into various sterols, such as cholesterol, by a multi-step pathway [78].…”