Mark Czekaj

Constrained β-alanine based GpIIb/IIIa antagonists

The concepts of centrally constrained and peptide based fibrinogen receptor antagonists have been successfully combined into a single series of analogs which have been demonstrated to be potent inhibitors of platelet aggregation.

Amido-(propyl and allyl)-hydroxybenzamidines: development of achiral inhibitors of factor Xa

The design, synthesis and SAR of amido-(propyl and allyl)-hydroxybenzamidine coagulation factor Xa inhibitors is described. These achiral inhibitors are selective for fXa vis a vis structurally related serine proteases and are readily prepared in 6-7 linear steps. The most potent member 9j (fXa Ki = 0.75 nM) is selective (>1000-fold) and an effective anticoagulant in mammalian plasma.

Non-peptide fibrinogen receptor antagonists based upon a 4-substituted piperidine scaffold

Abstract Structure-activity relationships developed from work with peptide based fibrinogen receptor antagonists have been successfully applied to the development of simple and highly potent nonpeptide agents of the same class.

Conformationally flexible platelet aggregation inhibitors based on the tetrapeptide Arg-Gly-Asp-Arg

Summary A series of nonpeptide fibrinogen receptor antagonists based upon the tetrapeptide Arg-Gly-Asp-Arg were prepared. These relatively simple derivatives incorporate a high degree of conformational flexibility that was anticipated to allow them to attain the requisite conformation for binding to the platelet fibrinogen receptor. Optimization of the distances between the required acidic and basic functional groups led eventually to compound 7, which is a one hundred-fold more potent inhibitor of platelet aggregation than the peptide it is based upon.