Orally Active Thrombin Inhibitors. Part 1. Optimization of the P1‐Moiety.

Mack, Helmut; Baucke, Dorit; Hornberger, Wilfried; Lange, Udo E. W.; Seitz, Werner; Hoeffken, H.W.

doi:10.1002/chin.200633201

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“…However, this protease is known as a key enzyme of the coagulation that links both intrinsic and extrinsic pathways of coagulation cascade (Moser and Patterson, 2003;Steinberg, 2005;Osipov et al, 2010). Thrombin (or factor IIa) is generated from prothrombin by the action of a complex of factors Xa and V, calcium ions, and phospholipids (Mack et al, 2006). The conversion of factor II or prothrombin in IIa is result of a series of zymogens activation by proteolysis, and thrombin is an effector and also a modulator of its crucial own generation (Lecompte et al, 2009).…”

Section: Review Looking Into a Serine Protease: Thrombinmentioning

confidence: 99%

Looking at the proteases from a simple perspective

Castro

Abreu

Geraldo

et al. 2011

J of Molecular Recognition

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Proteases have received enormous interest from the research and medical communities because of their significant roles in several human diseases. Some examples include the involvement of thrombin in thrombosis, HIV-1 protease in Acquired Immune Deficiency Syndrome, cruzain in Trypanosoma cruzi infection, and membrane-type 1 matrix metalloproteinase in tumor invasion and metastasis. Many efforts has been undertaken to design effective inhibitors featuring potent inhibitory activity, specificity, and metabolic stability to those proteases involved in such pathologies. Protease inhibitors usually target the active site, but some of them act by other inhibitory mechanisms. The understanding of the structure-function relationships of proteases and inhibitors has an impact on new inhibitor drugs designing. In this paper, the structures of four proteases (thrombin, HIV-protease, cruzain, and a matrix metalloproteinase) are briefly reviewed, and used as examples of the importance of proteases for the development of new treatment strategies, leading to a longer and healthier life.

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