FIXa is a serine protease enzyme involved in the intrinsic pathway of the coagulation cascade. The upstream intervention of the coagulation cascade in selectively inhibiting FIXa would leave hemostasis intact via the extrinsic pathway, leading to an optimum combination of efficacy and safety with low incidence of bleeding. We have identified 2-amindinobenzothiophene template as a lead scaffold for FIXa inhibiton based on its homology with urokinase plasminogen activator (uPA). Subsequent SAR work on the template revealed a number of highly potent FIXa inhibitors, though with moderate selectivity against FXa. X-ray study with one of the analogues demonstrated active site binding interaction with the induced opening of the S1 beta pocket and a secondary binding at the S2-S4 sites, which is in direct contrast with the previous finding.

On the basis of our understanding on the binding interactions of the benzothiophene template within the FIXa active site by X-ray crystallography and molecular modeling studies, we developed our SAR strategy by targeting the 4-position of the template to access the S1 beta and S2-S4 sites. A number of highly selective and potent factor Xa (FXa) and FIXa inhibitors were identified by simple switch of functional groups with conformational changes toward the S2-S4 sites.

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Synthesis of 9-Fluorenylmethyl Esters Using 9-Fluorenylmethyl Chloroformate.-In the presence of (iPr) 2 NEt as base and catalytic amounts of DMAP, N-Boc protected amino acids are directly converted to the related esters by 9-fluorenylmethyl chloroformate without racemization. The products are suitable substrates in solid-phase syntheses.-(MERETTE, S. A. M.; BURD, A. P.; DEADMAN, J. J.; Tetrahedron Lett. 40 (1999) 4, 753-754; Thrombosis Res. Inst., Emmanuel Kaye Build., Chelsea, London SW3 6LR, UK; EN)