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Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors.

Quan ML, Wong PC, Wang C, Woerner F, Smallheer JM, Barbera FA, Bozarth JM, Brown RL, Harpel MR, Luettgen JM, Morin PE, Peterson T, Ramamurthy V, Rendina AR, Rossi KA, Watson CA, Wei A, Zhang G, Seiffert D, Wexler RR
J Med Chem 57 955-69 (2014)
Related entries: 4na7, 4na9

Cited: 30 times
EuropePMC logo PMID: 24405333

Abstract

Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound 1 was identified as a potent and selective tool compound for proof of concept studies. It exhibited excellent antithrombotic efficacy in rabbit thrombosis models and did not prolong bleeding times. This demonstrates proof of concept for the FXIa mechanism in animal models with a reversible, small molecule inhibitor.

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Reviews citing this publication (8)

  1. Factors XI and XII as Targets for New Anticoagulants. Weitz JI, Fredenburgh JC. Front Med (Lausanne) 4 19 (2017)
  2. Emerging anticoagulant strategies. Fredenburgh JC, Gross PL, Weitz JI. Blood 129 147-154 (2017)
  3. New developments in anticoagulants: Past, present and future. Weitz JI, Harenberg J. Thromb Haemost 117 1283-1288 (2017)
  4. Factor XIa inhibitors: A review of the patent literature. Al-Horani RA, Desai UR. Expert Opin Ther Pat 26 323-345 (2016)
  5. Recent advances in the discovery and development of factor XI/XIa inhibitors. Al-Horani RA, Afosah DK. Med Res Rev 38 1974-2023 (2018)
  6. 2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis: Factor XI as a Target for New Anticoagulants. Weitz JI, Fredenburgh JC. Arterioscler Thromb Vasc Biol 38 304-310 (2018)
  7. Factor XI as a target for antithrombotic therapy. Bane CE, Gailani D. Drug Discov Today 19 1454-1458 (2014)
  8. Future prospects for contact factors as therapeutic targets. Gailani D. Hematology Am Soc Hematol Educ Program 2014 52-59 (2014)

Articles citing this publication (21)

  1. Designing allosteric inhibitors of factor XIa. Lessons from the interactions of sulfated pentagalloylglucopyranosides. Al-Horani RA, Desai UR. J Med Chem 57 4805-4818 (2014)
  2. A synthetic heparin mimetic that allosterically inhibits factor XIa and reduces thrombosis in vivo without enhanced risk of bleeding. Al-Horani RA, Abdelfadiel EI, Afosah DK, Morla S, Sistla JC, Mohammed B, Martin EJ, Sakagami M, Brophy DF, Desai UR. J Thromb Haemost 17 2110-2122 (2019)
  3. In vitro, antithrombotic and bleeding time studies of BMS-654457, a small-molecule, reversible and direct inhibitor of factor XIa. Wong PC, Quan ML, Watson CA, Crain EJ, Harpel MR, Rendina AR, Luettgen JM, Wexler RR, Schumacher WA, Seiffert DA. J Thromb Thrombolysis 40 416-423 (2015)
  4. Creating novel activated factor XI inhibitors through fragment based lead generation and structure aided drug design. Fjellström O, Akkaya S, Beisel HG, Eriksson PO, Erixon K, Gustafsson D, Jurva U, Kang D, Karis D, Knecht W, Nerme V, Nilsson I, Olsson T, Redzic A, Roth R, Sandmark J, Tigerström A, Öster L. PLoS One 10 e0113705 (2015)
  5. Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation. Santana-Romo F, Lagos CF, Duarte Y, Castillo F, Moglie Y, Maestro MA, Charbe N, Zacconi FC. Molecules 25 E491 (2020)
  6. Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties. Pinto DJ, Smallheer JM, Corte JR, Austin EJ, Wang C, Fang T, Smith LM, Rossi KA, Rendina AR, Bozarth JM, Zhang G, Wei A, Ramamurthy V, Sheriff S, Myers JE, Morin PE, Luettgen JM, Seiffert DA, Quan ML, Wexler RR. Bioorg Med Chem Lett 25 1635-1642 (2015)
  7. Design, synthesis and biological evaluation of PSMA/hepsin-targeted heterobivalent ligands. Subedi M, Minn I, Chen J, Kim Y, Ok K, Jung YW, Pomper MG, Byun Y. Eur J Med Chem 118 208-218 (2016)
  8. Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-ij]Quinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa. Novichikhina N, Ilin I, Tashchilova A, Sulimov A, Kutov D, Ledenyova I, Krysin M, Shikhaliev K, Gantseva A, Gantseva E, Podoplelova N, Sulimov V. Molecules 25 E1889 (2020)
  9. Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1H)-one as the P2' Moiety. Hu Z, Wong PC, Gilligan PJ, Han W, Pabbisetty KB, Bozarth JM, Crain EJ, Harper T, Luettgen JM, Myers JE, Ramamurthy V, Rossi KA, Sheriff S, Watson CA, Wei A, Zheng JJ, Seiffert DA, Wexler RR, Quan ML. ACS Med Chem Lett 6 590-595 (2015)
  10. Exploring the structure-activity relationships of ABCC2 modulators using a screening approach. Wissel G, Kudryavtsev P, Ghemtio L, Tammela P, Wipf P, Yliperttula M, Finel M, Urtti A, Kidron H, Xhaard H. Bioorg Med Chem 23 3513-3525 (2015)
  11. Novel phenylalanine derived diamides as Factor XIa inhibitors. Smith LM, Orwat MJ, Hu Z, Han W, Wang C, Rossi KA, Gilligan PJ, Pabbisetty KB, Osuna H, Corte JR, Rendina AR, Luettgen JM, Wong PC, Narayanan R, Harper TW, Bozarth JM, Crain EJ, Wei A, Ramamurthy V, Morin PE, Xin B, Zheng J, Seiffert DA, Quan ML, Lam PYS, Wexler RR, Pinto DJP. Bioorg Med Chem Lett 26 472-478 (2016)
  12. Pyridine and pyridinone-based factor XIa inhibitors. Corte JR, Fang T, Hangeland JJ, Friends TJ, Rendina AR, Luettgen JM, Bozarth JM, Barbera FA, Rossi KA, Wei A, Ramamurthy V, Morin PE, Seiffert DA, Wexler RR, Quan ML. Bioorg Med Chem Lett 25 925-930 (2015)
  13. Tetrahydroquinolines by the multicomponent Povarov reaction in water: calix[n]arene-catalysed cascade process and mechanistic insights. Rezende TRM, Varejão JOS, Sousa ALLA, Castañeda SMB, Fernandes SA. Org Biomol Chem 17 2913-2922 (2019)
  14. Macrocyclic inhibitors of Factor XIa: Discovery of alkyl-substituted macrocyclic amide linkers with improved potency. Corte JR, Yang W, Fang T, Wang Y, Osuna H, Lai A, Ewing WR, Rossi KA, Myers JE, Sheriff S, Lou Z, Zheng JJ, Harper TW, Bozarth JM, Wu Y, Luettgen JM, Seiffert DA, Quan ML, Wexler RR, Lam PYS. Bioorg Med Chem Lett 27 3833-3839 (2017)
  15. Discovery and Design of First Benzylamine-Based Ligands Binding to an Unlocked Conformation of the Complement Factor D. Vulpetti A, Ostermann N, Randl S, Yoon T, Mac Sweeney A, Cumin F, Lorthiois E, Rüdisser S, Erbel P, Maibaum J. ACS Med Chem Lett 9 490-495 (2018)
  16. Improved efficacy/safety profile of factor XIa inhibitor BMS-724296 versus factor Xa inhibitor apixaban and thrombin inhibitor dabigatran in cynomolgus monkeys. Wong PC, Quan ML. Res Pract Thromb Haemost 5 e12524 (2021)
  17. Macrocyclic factor XIa inhibitors. Wang C, Corte JR, Rossi KA, Bozarth JM, Wu Y, Sheriff S, Myers JE, Luettgen JM, Seiffert DA, Wexler RR, Quan ML. Bioorg Med Chem Lett 27 4056-4060 (2017)
  18. Enantioselective synthesis and selective functionalization of 4-aminotetrahydroquinolines as novel GLP-1 secretagogues. Kazancioglu MZ, Quirion K, Wipf P, Skoda EM. Chirality 34 521-536 (2022)
  19. New Hybrid Tetrahydropyrrolo[3,2,1-ij]quinolin-1-ylidene-2-thioxothiazolidin-4-ones as New Inhibitors of Factor Xa and Factor XIa: Design, Synthesis, and In Silico and Experimental Evaluation. Novichikhina NP, Shestakov AS, Medvedeva SM, Lagutina AM, Krysin MY, Podoplelova NA, Panteleev MA, Ilin IS, Sulimov AV, Tashchilova AS, Sulimov VB, Geronikaki A, Shikhaliev KS. Molecules 28 3851 (2023)
  20. Design, Synthesis, and Evaluation of New Hybrid Derivatives of 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one as Potential Dual Inhibitors of Blood Coagulation Factors Xa and XIa. Skoptsova AA, Geronikaki A, Novichikhina NP, Sulimov AV, Ilin IS, Sulimov VB, Bykov GA, Podoplelova NA, Pyankov OV, Shikhaliev KS. Molecules 29 373 (2024)
  21. Identifying new clotting factor XIa inhibitors in virtual high-throughput screens using PCA-GA-SVM models and signature. Chen JJ, Schmucker LN, Visco DP. Biotechnol Prog 34 1553-1565 (2018)


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