ArticleJournal of medicinal chemistry2011
Rational design of potent, small, synthetic allosteric inhibitors of thrombin.
Article in Journal of medicinal chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
27 citing papers in PubMed, 54 citations in OpenAlex.
- Fully Synthetic Non-Carbohydrate Heparin Mimetics-Perspectives for Therapeutic Anticoagulation and Beyond?Archiv der Pharmazie · 2026Review
- Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G.Biomolecules · 2023Article
- Designing Smaller, Synthetic, Functional Mimetics of Sulfated Glycosaminoglycans as Allosteric Modulators of Coagulation Factors.Journal of medicinal chemistry · 2023Review
- Designing Synthetic, Sulfated Glycosaminoglycan Mimetics That Are Orally Bioavailable and ExhibitingJournal of medicinal chemistry · 2023Article
- Sulfated Non-Saccharide Glycosaminoglycan Mimetics as Novel Drug Discovery Platform for Various Pathologies.Current medicinal chemistry · 2020Review
- Thrombin Exosite Maturation and Ligand Binding at ABE II Help Stabilize PAR-Binding Competent Conformation at ABE I.Biochemistry · 2019Article
- Novel heparin mimetics reveal cooperativity between exosite 2 and sodium-binding site of thrombin.Thrombosis research · 2018Article
- A small group of sulfated benzofurans induces steady-state submaximal inhibition of thrombin.Bioorganic & medicinal chemistry letters · 2018Article
- Deciphering Conformational Changes Associated with the Maturation of Thrombin Anion Binding Exosite I.Biochemistry · 2017Article
- Allosteric Partial Inhibition of Monomeric Proteases. Sulfated Coumarins Induce Regulation, not just Inhibition, of Thrombin.Scientific reports · 2016Article
- Allosterism-based simultaneous, dual anticoagulant and antiplatelet action: allosteric inhibitor targeting the glycoprotein Ibα-binding and heparin-binding site of thrombin.Journal of thrombosis and haemostasis : JTH · 2016Article
- Potent inhibition of enterovirus D68 and human rhinoviruses by dipeptidyl aldehydes and α-ketoamides.Antiviral research · 2016Article
- Development of Orally Active Thrombin Inhibitors for the Treatment of Thrombotic Disorder Diseases.Molecules (Basel, Switzerland) · 2015Review
- Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies.Journal of medicinal chemistry · 2015Article
- Plasmin regulation through allosteric, sulfated, small molecules.Molecules (Basel, Switzerland) · 2015Article
- Substantial non-electrostatic forces are needed to induce allosteric disruption of thrombin's active site through exosite 2.Biochemical and biophysical research communications · 2014Article
- Designing allosteric inhibitors of factor XIa. Lessons from the interactions of sulfated pentagalloylglucopyranosides.Journal of medicinal chemistry · 2014Article
- Allosteric inhibition of human factor XIa: discovery of monosulfated benzofurans as a class of promising inhibitors.Journal of medicinal chemistry · 2014Article
- Targeting the GPIbα binding site of thrombin to simultaneously induce dual anticoagulant and antiplatelet effects.Journal of medicinal chemistry · 2014Article
- Potent inhibition of norovirus by dipeptidyl α-hydroxyphosphonate transition state mimics.Bioorganic & medicinal chemistry letters · 2013Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
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 IC(50) 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.