Progress in Drug Development

Historic approaches to anticoagulation have relied on partially purified or chemically derivatized natural products, such as heparin and warfarin. The utility of these agents, however, is limited by interpatient variability in pharmacologic effect, the requirement for laboratory monitoring, and, for warfarin, various food and drug interactions. The association of heparin and warfarin with prothrombotic complications—immune heparin-induced thrombocytopenia (HIT) and warfarin necrosis—are particularly troublesome.

Many novel anticoagulants are under clinical development (Weitz, 2006; Bates and Weitz, 2006). For example, initiation of coagulation by the tissue factor: factor VIIa (TF/VIIa) complex has been targeted by recombinant proteins, such as nematode anticoagulant peptide c2 (rNAPc2; Nuvelo Inc., San Carlos, CA), tissue factor pathway inhibitor (tifacogin; Pfizer Corporation, New York, NY) and inactivated factor VIIa (VIIai; Novo Nordisk A/S, Gentofte, Denmark). In contrast, inhibition of factor IXa has been pursued using a targeted small molecule (TTP889; TransTech Pharma, High Point, NC), a pair of single-stranded DNA aptamers (REG1; Regado Biosciences, Research Triangle Park, NC) and humanized monoclonal antibodies (SB 249417; GlaxoSmithKline Pharmaceuticals, King of Prussia, PA). As these agents are in early development primarily for sepsis and acute coronary syndrome (ACS), they will not be considered further.

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