Chuen Chan

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 : 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.

Spiro-piperidine non-peptide neurokinin-1 receptor antagonists

Abstract The synthesis and activity of a novel spiro-piperidine non-peptide antagonist (2) of the neurokinin-1 (NK 1 ) receptor is described. Despite having essentially the same solution conformation as CP 99,994 (1) at physiological pH, (2) has reduced affinity for the NK 1 receptor.

The squalestatins: cleavage of the bicyclic core via the novel 6,8-dioxabicyclo[3.2.1]octane ring system

Squalestatin S1 1 has been converted into its 4,7-bis(2-methoxyethoxymethyl)ether 4,5-dimethyl ester 11 and thence to its 3-(tert-butoxycarbonyl)amino derivative 12via a Schmidt degradation. Acid-catalysed hydrolysis of 12 brought about a molecular rearrangement of the 2,8-dioxa- to the novel 6,8-dioxa-bicyclo[3.2.1]octane ring system 3. Oxidation of 3 followed by methanolysis gave the novel spiroketal 17. Treatment of 3 with trimethyl phosphonoacetate gave the acyclic derivative 18.

The squalestatins: Synthesis of c-4 carboxamide derivatives

Abstract Synthesis of squalcstalin S1 C-4 carboxamide, 2, as well as related C-4 amides and C-4 hydroxymethyl derivatives possessing a C-3 hydroxymethyl group (15 and 19) together with their SQS inhibitory activities arc presented.