There has been a revolution in the development of effective, small-molecule 
anticoagulants and antiplatelet agents. Numerous trypsin-like serine proteases 
have been under active pursuit as therapeutic targets. Important examples 
include thrombin, factor VIIa, factor Xa, and β-tryptase with indications 
ranging from thrombosis and inflammation to asthma and chronic obstructive 
pulmonary disease (COPD). Trypsin-like serine proteases exhibit a highly similar 
tertiary folding pattern, especially for the region near the substrate binding 
pocket that includes the conserved catalytic triad consisting of histidine 57, 
aspartic acid 102, and serine 195. A rich collection of X-ray structures for 
many trypsin-like serine proteases is available, which greatly facilitated the 
optimization of small organic inhibitors as therapeutic agents. The present 
review surveyed those inhibitors disclosed in peer-reviewed scientific journals 
and patent publications with a special focus on structural features and 
protein-inhibitor interactions that implicated the inhibitor optimization 
process. The role played by the residue 190 of trypsin-like serine proteases is 
critical. While many inhibitors without a basic group have progressed into the 
clinic for ones with alanine 190, the task for those with serine 190 remains 
extremely challenging, if not impossible. In addition to warfarin, heparin, and 
low molecular weight heparins (LMWHs), treatment options have expanded with the 
development and approval of the new oral anticoagulants (NOACs). The NOACs are 
superior to vitamin K antagonists in terms of rapid onset, pharmacokinetics, 
drug/food interactions, and regular coagulation monitoring; but one serious 
drawback is the lack of an effective antidote at this time. Apixaban (Eliquis), 
rivaroxaban (Xarelto), and edoxaban (Savaysa) are the new Xa inhibitors that 
have been recently approved by the U.S. FDA and are in current clinical 
practice. These drugs bind to the active site of factor Xa (fXa) which prevents 
the conversion of prothrombin to thrombin. In addition, dabigatran etexikate 
(Pradaxa), the direct thrombin inhibitor (fIIa) is also now widely prescribed.