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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)
Related entries: 4na7, 4na8, 4na9, 4ty6, 4ty7, 4wxi, 4x6m, 4x6n, 4x6o, 4x6p, 4y8x, 4y8y, 4y8z, 5e2o, 5e2p, 5exl, 5exm, 5exn, 5q0d, 5q0f, 5q0g, 5q0h, 5tks, 5tkt, 5tku

Cited: 3 times
EuropePMC logo PMID: 28687203

Abstract

Optimization of macrocyclic inhibitors of FXIa is described which focused on modifications to both the macrocyclic linker and the P1 group. Increases in potency were discovered through interactions with a key hydrophobic region near the S1 prime pocket by substitution of the macrocyclic linker with small alkyl groups. Both the position of substitution and the absolute stereochemistry of the alkyl groups on the macrocyclic linker which led to improved potency varied depending on the ring size of the macrocycle. Replacement of the chlorophenyltetrazole cinnamide P1 in these optimized macrocycles reduced the polar surface area and improved the oral bioavailability for the series, albeit at the cost of a decrease in potency.

Reviews citing this publication (2)

  1. Discovery methods of coagulation-inhibiting drugs. Gómez-Outes A, García-Fuentes M, Suárez-Gea ML. Expert Opin Drug Discov 12 1195-1205 (2017)
  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 (1)

  1. Studies on fragment-based design of allosteric inhibitors of human factor XIa. Boothello RS, Sankaranarayanan NV, Afosah DK, Karuturi R, Al-Horani RA, Desai UR. Bioorg Med Chem 28 115762 (2020)


Related citations provided by authors (8)

  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 57 955-69 (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 9915-32 (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 25 925-30 (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)
  5. 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)
  6. 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)
  7. Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors: Discovery of the methyl N-phenyl carbamate P2 prime group.. Corte JR, Fang T, Pinto DJ, Orwat MJ, Rendina AR, Luettgen JM, Rossi KA, Wei A, Ramamurthy V, Myers JE, Sheriff S, Narayanan R, Harper TW, Zheng JJ, Li YX, Seiffert DA, Wexler RR, Quan ML Bioorg Med Chem 24 2257-72 (2016)
  8. Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker.. Corte JR, Fang T, Osuna H, Pinto DJ, Rossi KA, Myers JE, Sheriff S, Lou Z, Zheng JJ, Harper TW, Bozarth JM, Wu Y, Luettgen JM, Seiffert DA, Decicco CP, Wexler RR, Quan ML J Med Chem 60 1060-1075 (2017)

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