A small group of sulfated benzofurans induces steady-state submaximal inhibition of thrombin

[Display omitted] Despite the development of promising direct oral anticoagulants, which are all orthosteric inhibitors, a sizable number of patients suffer from bleeding complications. We have hypothesized that allosterism based on the heparin-binding exosites presents a major opportunity to induce...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2018-04, Vol.28 (6), p.1101-1105
Main Authors: Afosah, Daniel K., Verespy, Stephen, Al-Horani, Rami A., Boothello, Rio S., Karuturi, Rajesh, Desai, Umesh R.
Format: Article
Language:English
Subjects:
Allosteric inhibition
Anticoagulants
Benzofurans - chemical synthesis
Benzofurans - chemistry
Benzofurans - pharmacology
Dose-Response Relationship, Drug
Enzyme regulation
Heparin-binding site
Humans
Molecular Structure
Serine Proteinase Inhibitors - chemical synthesis
Serine Proteinase Inhibitors - chemistry
Serine Proteinase Inhibitors - pharmacology
Small Molecule Libraries - chemical synthesis
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Structure-Activity Relationship
Sulfates - chemistry
Sulfates - pharmacology
Thrombin
Thrombin - antagonists & inhibitors
Thrombin - metabolism
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Summary:[Display omitted] Despite the development of promising direct oral anticoagulants, which are all orthosteric inhibitors, a sizable number of patients suffer from bleeding complications. We have hypothesized that allosterism based on the heparin-binding exosites presents a major opportunity to induce sub-maximal inhibition of coagulation proteases, thereby avoiding/reducing bleeding risk. We present the design of a group of sulfated benzofuran dimers that display heparin-binding site-dependent partial allosteric inhibition of thrombin against fibrinogen (ΔY = 55–75%), the first time that a small molecule (MW  
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2018.01.069