Chapter 9. Factor Xa inhibitors: Recent advances in anticoagulant agents

Abstract

Publisher Summary This chapter focuses on the advances reported in 1999 in the design and discovery of novel factor Xa inhibitors as potential orally active anticoagulants. Factor Xa is a trypsin-like serine protease, which plays a pivotal role in the blood coagulation cascade. Factor Xa is at the final convergence point of both intrinsic and extrinsic coagulation pathways. A number of series of novel and structurally simple non-benzamidine factor Xa inhibitors have been discovered that inhibit factor Xa and factor Xa in the prothrombinase complex with low nM potency. These inhibitors do not inhibit any other trypsin-like serine proteinases such as thrombin, trypsin, APC, plasmin, t-PA, urokinase, and kallikrein. Some of the nonbenzamidine factor Xa inhibitors show the desired pharmacokinetic properties and have antithrombotic effects in animal thrombosis models as well. Several new molecules, such as ZD-4927 and DPC-423, have advanced into clinical trials as oral agents. ZK-807834 is under clinical investigation as an intravenous agent. Diamidino and dibasic factor Xa inhibitors are discussed in the chapter. Mono-benzamidine and non-benzamidine factor Xa inhibitors are elaborated and drug design perspective and issues are also discussed.