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5-Chlorothiophene-2-carboxylic acid [(S)-2-[2-methyl-3-(2-oxopyrrolidin-1-yl)benzenesulfonylamino]-3-(4-methylpiperazin-1-yl)-3-oxopropyl]amide (SAR107375), a selective and potent orally active dual thrombin and factor Xa inhibitor.

Meneyrol J, Follmann M, Lassalle G, Wehner V, Barre G, Rousseaux T, Altenburger JM, Petit F, Bocskei Z, Schreuder H, Alet N, Herault JP, Millet L, Dol F, Florian P, Schaeffer P, Sadoun F, Klieber S, Briot C, Bono F, Herbert JM
J Med Chem 56 9441-56 (2013)
Related entries: 4bti, 4btt, 4btu, 4lxb

Cited: 9 times
EuropePMC logo PMID: 24175584

Abstract

Compound 15 (SAR107375), a novel potent dual thrombin and factor Xa inhibitor resulted from a rational optimization process. Starting from compound 14, with low factor Xa and modest anti-thrombin inhibitory activities (IC50's of 3.5 and 0.39 μM, respectively), both activities were considerably improved, notably through the incorporation of a neutral chlorothiophene P1 fragment and tuning of P2 and P3-P4 fragments. Final optimization of metabolic stability with microsomes led to the identification of 15, which displays strong activity in vitro vs factor Xa and thrombin (with Ki's of 1 and 8 nM, respectively). In addition 15 presents good selectivity versus related serine proteases (roughly 300-fold), including trypsin (1000-fold), and is very active (0.39 μM) in the thrombin generation time (TGT) coagulation assay in human platelet rich plasma (PRP). Potent in vivo activity in a rat model of venous thrombosis following iv and, more importantly, po administration was also observed (ED50 of 0.07 and 2.8 mg/kg, respectively). Bleeding liability was reduced in the rat wire coil model, more relevant to arterial thrombosis, with 15 (blood loss increase of 2-fold relative to the ED80 value) compared to rivaroxaban 2 and dabigatran etexilate 1a.

Articles - 4loy mentioned but not cited (1)

  1. Pyrazole-Based Thrombin Inhibitors with a Serine-Trapping Mechanism of Action: Synthesis and Biological Activity. Dunker C, Imberg L, Siutkina AI, Erbacher C, Daniliuc CG, Karst U, Kalinin DV. Pharmaceuticals (Basel) 15 1340 (2022)


Reviews citing this publication (3)

  1. Development of Orally Active Thrombin Inhibitors for the Treatment of Thrombotic Disorder Diseases. He LW, Dai WC, Li NG. Molecules 20 11046-11062 (2015)
  2. Structure-activity relationship studies for multitarget antithrombotic drugs. Neves AR, Correia-da-Silva M, Sousa E, Pinto M. Future Med Chem 8 2305-2355 (2016)
  3. Prolinamide derivatives as thrombin inhibitors for the treatment of thrombin-mediated diseases: a patent evaluation of US2013296245. Shi ZH, Li NG, Tang YP, Duan JA. Expert Opin Ther Pat 24 1139-1148 (2014)

Articles citing this publication (5)

  1. Is It Reliable to Take the Molecular Docking Top Scoring Position as the Best Solution without Considering Available Structural Data? Ramírez D, Caballero J. Molecules 23 (2018)
  2. Theoretical Study of Molecular Structure and Physicochemical Properties of Novel Factor Xa Inhibitors and Dual Factor Xa and Factor IIa Inhibitors. Remko M, Remková A, Broer R. Molecules 21 (2016)
  3. 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 (2020)
  4. Novel FXa Inhibitor Identification through Integration of Ligand- and Structure-Based Approaches. Lagos CF, Segovia GF, Nuñez-Navarro N, Faúndez MA, Zacconi FC. Molecules 22 (2017)
  5. Synthesis and Thrombin, Factor Xa and U46619 Inhibitory Effects of Non-Amidino and Amidino N²-Thiophenecarbonyl- and N²-Tosylanthranilamides. Lee SH, Lee W, Nguyen T, Um IS, Bae JS, Ma E. Int J Mol Sci 18 (2017)


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