ArticleJournal of thrombosis and haemostasis : JTH2019
A synthetic heparin mimetic that allosterically inhibits factor XIa and reduces thrombosis in vivo without enhanced risk of bleeding.
Article in Journal of thrombosis and haemostasis : JTH, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 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
24 citing papers in PubMed, 33 citations in OpenAlex.
- First randomized evaluation of safety, pharmacodynamics, and pharmacokinetics of BAY 1831865, an antibody targeting coagulation factor XI and factor XIa, in healthy men.Journal of thrombosis and haemostasis : JTH · 2022Trial
- Translational Development of Oral FXIa Inhibitors: A Systematic Review of Molecular Design, Pharmacology, and Indication-Specific Clinical Evidence.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Chemical Synthesis and Biochemical Evaluation of Decasulfated Galloylglucopyranose Heparin Mimetic.Cardiovascular & hematological agents in medicinal chemistry · 2026Article
- Fully Synthetic Non-Carbohydrate Heparin Mimetics-Perspectives for Therapeutic Anticoagulation and Beyond?Archiv der Pharmazie · 2026Review
- Antithrombotic Polymers: A Narrative Review on Current and Future Strategies for Their Design, Synthesis, and Application.International journal of molecular sciences · 2026Review
- Emerging Targets, Novel Directions, and Innovative Approaches in Thrombosis Therapy.Aging and disease · 2025Review
- A Robust Proteomics-Based Method for Identifying Preferred Protein Targets of Synthetic Glycosaminoglycan Mimetics.bioRxiv : the preprint server for biology · 2025Article
- Sulfonated Penta-galloyl Glucose (SPGG): The Pharmacological Effects of Promiscuous Glycosaminoglycan Small Molecule Mimetic.Mini reviews in medicinal chemistry · 2025Review
- Development of an Ultrasensitive Competitive Double-Enzyme Cascade Fluorescence Signal Amplification Method for Factor XIa Inhibitor Screening.Analytical chemistry · 2024Article
- Merging cultures and disciplines to create a drug discovery ecosystem at Virginia commonwealth university: Medicinal chemistry, structural biology, molecular and behavioral pharmacology and computational chemistry.SLAS discovery : advancing life sciences R & D · 2023Review
- Investigation of the anticoagulant activity of cyclic sulfated glycosaminoglycan mimetics.Carbohydrate research · 2023Article
- 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
- Heparin Mimetics and Their Impact on Extracellular Matrix Protein Assemblies.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Designing Synthetic, Sulfated Glycosaminoglycan Mimetics That Are Orally Bioavailable and ExhibitingJournal of medicinal chemistry · 2023Article
- Nanobodies against factor XI apple 3 domain inhibit binding of factor IX and reveal a novel binding site for high molecular weight kininogen.Journal of thrombosis and haemostasis : JTH · 2022Article
- Sulfonated non-saccharide molecules and human factor XIa: Enzyme inhibition and computational studies.Chemical biology & drug design · 2022Article
- Studies on fragment-based design of allosteric inhibitors of human factor XIa.Bioorganic & medicinal chemistry · 2020Article
- Discovery of Benzyl Tetraphosphonate Derivative as Inhibitor of Human Factor Xia.ChemistryOpen · 2020Article
- The rebirth of the contact pathway: a new therapeutic target.Current opinion in hematology · 2020Review
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
backgroundHuman factor XIa (FXIa) is an actively pursued target for development of safer anticoagulants. Our long-standing hypothesis has been that allosterism originating from heparin-binding site(s) on coagulation enzymes is a promising approach to yield safer agents.
objectivesTo develop a synthetic heparin mimetic as an inhibitor of FXIa so as to reduce clot formation in vivo but not carry high bleeding risk.
methodsWe employed a gamut of methods involving synthetic chemistry, biophysical biochemistry, enzyme assays, blood and plasma coagulation assays, and in vivo thrombosis models in this work.
resultsSulfated chiro-inositol (SCI), a non-saccharide mimetic of heparin, was synthesized in three steps in overall yields of >50%. SCI inhibited FXIa with potency of 280 nmol/L and preferentially engaged FXIa's heparin-binding site to conformationally alter its active site. SCI inhibition of FXIa could be rapidly reversed by common antidotes, such as protamine. SCI preferentially prolonged plasma clotting initiated with recalcification, rather than thromboplastin, alluding to its intrinsic pathway-based mechanism. Human blood thromboelastography indicated good ex vivo anticoagulation properties of SCI. Rat tail bleeding and maximum-dose-tolerated studies indicated that no major bleeding or toxicity concerns for SCI suggesting a potentially safer anticoagulation outcome. FeCl
conclusionsOverall, SCI is a highly promising, allosteric inhibitor of FXIa that induces potent anticoagulation in vivo. Further studies are necessary to assess SCI in animal models mimicking human clinical indications.
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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.