Nigel S. Watson

Squalene synthase inhibitors : Their potential as hypocholesterolaemic agents

Publisher Summary This chapter discusses potential of squalene synthase inhibitors as hypocholesterolaemic agents. Hypercholesterolaemia is well recognized as a major independent risk factor for coronary disease and a number of studies have shown that reducing elevated levels of serum cholesterol in man leads to a reduction in the incidence of coronary-related deaths. Developments in the last few years have shown that one of the most effective approaches to treating hypercholesterolaemia is by inhibiting cholesterol biosynthesis. A number of clinically effective agents are available, such as lovastatin, simvastatin and pravastatin, which work by inhibiting HMGR, and these typically reduce serum cholesterol levels by 30% in man. Major toxic effects are not commonly associated with this class of compounds, and an improvement in survival has been demonstrated for patients with coronary heart disease by lowering their lipid levels with simvastatin. Squalene synthase inhibitors are the first committed step to sterol biosynthesis and inhibitors of this enzyme represent attractive potential new therapies for hypercholesterolaemia. The squalestatins (zaragozic acids) are potent, selective inhibitors of both the rat and fungal enzymes and exhibit potent broad-spectrum antifungal activity in vitro.

Structurally simplified squalestatins: A convenient route to a 67-unsubstituted derivative

Abstract The squalestatin 1 , has been converted into the 6,7-unsubstituted analogue, 3 , via inversion of the alcohol at C7, selective removal of the α,β-unsaturated ester at C6 followed by a Corey-Hopkins deoxygenation of the generated 6 R ,7 S -diol.

The squalestatins: C-3 Decarboxylation studies and rearrangement to the 6,8-dioxabicyclo[3.2.1]octane ring system

3-Decarboxy squalestatins 3 and 4 were synthesised via photolysis of t-butyl peroxyester 7. Lactol 10 was isolated unexpectedly from both HCl-dioxan cleavage of 8, a by-product of the photolysis, and attempted Barton decarboxylation of 6. In TFA under anhydrous conditions, 8 was converted to the tricyclic ether 11.

Antithrombotic potential of GW813893: a novel, orally active, active-site directed factor Xa inhibitor.

Background: Factor Xa (FXa) has been a target of considerable interest for drug development efforts aimed at suppressing thrombosis. In this report, a new orally active, small molecule, active-site directed FXa inhibitor, GW813893, has been profiled in a succession of in vitro and in vivo assays involved in its preclinical characterization as a potential antithrombotic therapeutic. Methods: In vitro profiling of GW813893 consisted of assessing its inhibitory potential against FXa and a broad panel of related and unrelated enzymes and receptors. Additionally, the FXa inhibition potential of GW813893 was assessed in prothrombinase and plasma-based clotting assays. In vivo characterization of GW813893 consisted of thrombosis studies in a rat inferior vena cava model, a rat carotid artery thrombosis model, and a rabbit jugular thrombosis model. Bleeding studies were conducted in a rat tail transection model. Ex vivo determinations of compound effects on FX and clotting activity were also undertaken. Results: GW813893 was more than 90-fold selective over all enzymes tested, and it inhibited FXa and prothrombinase activity with a Ki of 4.0 nM and 9.7 nM, respectively. In vivo, GW813893 concentration-dependently suppressed thrombotic activity in all models tested. The antithrombotic activity correlated with the suppression of plasma-based clotting activity and the inhibition of plasma FX activity (P < 0.02). Over the antithrombotic dose-range, an increased bleeding diathesis was not observed. Conclusion: These experiments demonstrate that GW813893 is a potent, selective, orally active inhibitor of FXa. The data suggest that GW813893 has robust antithrombotic potential at doses that have no detectable hemostasis liability. Collectively, the profile suggests that GW813893 has the preclinical pharmacology underpinnings of an oral antithrombotic therapeutic.

The squalestatins: Cleavage of the bicyclic core via the novel 2,8,9-trioxabicyclo[3.3.1]nonane ring system

Abstract Squalestatin 1 was converted into the γ-lactone analogue 5 , via hydrolysis of the novel ortho ester anhydride 3 , and thence into the acyclic derivative 8 .

The squalestatins : potent inhibitors of squalene synthase : the role of the tricarboxylic acid moiety

In squalestatins possessing at C6 either a 4,6-dimethyloctenoate ester or a hydroxyl group, the 5-carboxylic acid is crucial for squalene synthase inhibitory activity. In the former seires, free carboxylic acids are not required at C3 or C4 for potent enzyme inhibitory activity whereas in the latter series esterification of the carboxylic acids at C3 or C4 results in a significant reduction in enzyme inhibitory activity.

Conversion of clavulanic acid into thiadeoxa nuclear analogues

Abstract 1,4-Addition of sulphur nucleophiles to the diene ( 12 ) derived via the pen-2-em ( 5 ) from clavulanic acid provides the thiadeoxa analogues ( 14 – 15 ). X-ray analysis of the ester ( 14 ) shows the thermodynamically stable isomers to have the same relative stereochemistry as clavulanic acid.

The squalestatins: Potent inhibitors of squalene synthase, 3-hydroxymethyl derivatives.

A series of 3-hydroxymethyl derivatives of squalestatin 1 was prepared as inhibitors of squalene synthase. Potent in vitro inhibitory activity is retained in those analogues which possess C-6 and C-1 substituents analogous to those found in 1.

Structurally simplified squalestatins : monocyclic 1,3-dioxane analogues

Abstract Monocyclic analogues of squalestatin 1 based on a 1,3-dioxane ring were prepared and evaluated for their ability to inhibit squalene synthase in vitro. The compound 16a possessing a 4,6-dimethyloctenoyloxymethyl group at C4 and a carboxamide at C2 showed similar inhibitory activity to 1.

The squalestatins: novel inhibitors of squalene synthase. The optimal C1 chain-length requirements.

Abstract Analogues of squalestatin 1 modified in th C1 side-chain were prepared and evaluated for their ability to inhibit squalene synthase in vitro. An appropriately substituted 6-phenylhexyl chain was found to be optimal for effective enzyme inhibition.