John W. Bryant

Structure-based Drug Design of Pyrrolidine-1, 2-dicarboxamides as a Novel Series of Orally Bioavailable Factor Xa Inhibitors

A novel series of pyrrolidine‐1,2‐dicarboxamides was discovered as factor Xa inhibitors using structure‐based drug design. This series consisted of a neutral 4‐chlorophenylurea P1, a biphenylsulfonamide P4 and a d‐proline scaffold (1, IC50 = 18 nm). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC50 = 0.38 nm), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.

Biochemical characterization of a novel high-affinity and specific plasma kallikrein inhibitor

BACKGROUND AND PURPOSE Kallikrein acts on high molecular weight kininogen (HK) to generate HKa (cleaved HK) and bradykinin (BK). BK exerts its effects by binding to B2 receptors. The activation of B2 receptors leads to the formation of tissue plasminogen activator, nitric oxide (NO) and prostacyclin (PGI2). An elevated kallikrein‐dependent pathway has been linked to cardiovascular disease risk. The aim of this study was to investigate whether our novel plasma kallikrein inhibitor abolishes kallikrein‐mediated generation of BK from HK and subsequent BK‐induced NO and PGI2 formation, thereby influencing endothelial pathophysiology during chronic inflammatory diseases.