First steps in the direction of synthetic, allosteric, direct inhibitors of thrombin and factor Xa

作者：Verghese Jenson; Liang Aiye; Sidhu Preet Pal Singh; Hindle Michael; Zhou Qibing; Desai Umesh R^*

来源：Bioorganic & Medicinal Chemistry Letters, 2009, 19(15): 4126-4129.

DOI：10.1016/j.bmcl.2009.06.013

• Thrombin
• Factor Xa
• Inhibition
• Allosteric
• Synthetic small molecules
• Library
• Screening
• Lignins
• Dehydropolymers

Designing non-saccharide functional mimics of heparin is a major challenge. In this work, a library of small, aromatic molecules based on the sulfated DHP scaffold was synthesized and screened against thrombin and factor Xa. The results reveal that (i) selected monomeric benzofuran derivatives inhibit the two enzymes, albeit weakly; (ii) the two enzymes recognize different structural features in the benzofurans studied suggesting significant selectivity of recognition; and (iii) the mechanism of inhibition is allosteric. The molecules represent the. first allosteric small molecule inhibitors of the two enzymes.

• 出版日期2009-8-1