Preetpal Sidhu - Rational Design of Potent, Small, Synthetic Allosteric Inhibitors of Thrombin

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  Publication Details (including relevant citation   information):

  Preetpal Singh Sidhu, Aiye Liang, Akul Y. Mehta, May H. Abdel Aziz, Qibing Zhou§, and   Umesh R. Desai*


  Department of Medicinal   Chemistry and Institute for   Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond,   Virginia 23219, United States  

    Institute for Materia Medica, College of Life Science and     Technology, Huazhong University of     Science and Technology, Wuhan, Hubei 430074, P. R. China  


  Thrombin is a key enzyme targeted by the majority of current   anticoagulants that are direct inhibitors. Allosteric inhibition   of thrombin may offer a major advantage of finely tuned   regulation. We present here sulfated benzofurans as the first   examples of potent, small allosteric inhibitors of thrombin. A   sulfated benzofuran library of 15 sulfated monomers and 13   sulfated dimers with different charged, polar, and hydrophobic   substituents was studied in this work. Synthesis of the sulfated   benzofurans was achieved through a multiple step, highly branched   strategy, which culminated with microwave-assisted chemical   sulfation. Of the 28 potential inhibitors, 11 exhibited   reasonable inhibition of human α-thrombin at pH 7.4.   Structure–activity relationship analysis indicated that sulfation   at the 5-position of the benzofuran scaffold was essential for   targeting thrombin. A tert-butyl 5-sulfated benzofuran   derivative was found to be the most potent thrombin inhibitor   with an IC50 of 7.3 μM under   physiologically relevant conditions. Michaelis–Menten studies   showed an allosteric inhibition phenomenon. Plasma clotting   assays indicate that the sulfated benzofurans prolong both the   activated partial thromboplastin time and prothrombin time.   Overall, this work puts forward sulfated benzofurans as the first   small, synthetic molecules as powerful lead compounds for the   design of a new class of allosteric inhibitors of thrombin.

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