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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 6 590-5 (2015)
Related entries: 4x6m, 4x6n, 4x6o, 4x6p, 4y8x, 4y8z

Cited: 5 times
EuropePMC logo PMID: 26005539

Abstract

Structure-activity relationship optimization of phenylalanine P1' and P2' regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2' group enhanced FXIa affinity and metabolic stability. Incorporation of an N-methyl piperazine amide group to replace the phenylalanine improved both FXIa potency and aqueous solubility. Combination of the optimization led to the discovery of FXIa inhibitor 13 with a FXIa K i of 0.04 nM and an aPTT EC2x of 1.0 μM. Dose-dependent efficacy (EC50 of 0.53 μM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation.

Reviews citing this publication (2)

  1. Factor XIa inhibitors: A review of the patent literature. Al-Horani RA, Desai UR. Expert Opin Ther Pat 26 323-345 (2016)
  2. Recent advances in the discovery and development of factor XI/XIa inhibitors. Al-Horani RA, Afosah DK. Med Res Rev 38 1974-2023 (2018)

Articles citing this publication (3)

  1. 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)
  2. 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)
  3. 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)


Related citations provided by authors (4)

  1. 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. 57 955-969 (2014)
  2. Phenylimidazoles as Potent and Selective Inhibitors of Coagulation Factor XIa with In Vivo Antithrombotic Activity. Hangeland JJ, Friends TJ, Rossi KA, Smallheer JM, Wang C, Sun Z, Corte JR, Fang T, Wong PC, Rendina AR, Barbera FA, Bozarth JM, Luettgen JM, Watson CA, Zhang G, Wei A, Ramamurthy V, Morin PE, Bisacchi GS, Subramaniam S, Arunachalam P, Mathur A, Seiffert DA, Wexler RR, Quan ML J. Med. Chem. 57 9915-9932 (2014)
  3. 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)
  4. 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 1635-42 (2015)

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