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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:19

Article

Verghese, Jenson^1,2  Liang, Aiye^1,2  Sidhu, Preet Pal Singh¹  Hindle, Michael³  Zhou, Qibing⁴  Desai, Umesh R.^1,2 

[1] Virginia Commonwealth Univ, Dept Med Chem, Richmond, VA 23298 USA

[2] Virginia Commonwealth Univ, Inst Struct Biol & Drug Discovery, Richmond, VA 23298 USA

[3] Virginia Commonwealth Univ, Dept Pharmaceut, Richmond, VA 23298 USA

[4] Virginia Commonwealth Univ, Dept Chem, Richmond, VA 23298 USA

关键词: Thrombin;    Factor Xa;    Inhibition;    Allosteric;    Synthetic small molecules;    Library;    Screening;    Lignins;    Dehydropolymers;   

DOI  :  10.1016/j.bmcl.2009.06.013

来源: Elsevier

【 摘 要 】

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. (C) 2009 Elsevier Ltd. All rights reserved.

【 授权许可】

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