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Design and synthesis of orally active pyrrolidin-2-one-based factor Xa inhibitors.

Watson NS, Brown D, Campbell M, Chan C, Chaudry L, Convery MA, Fenwick R, Hamblin JN, Haslam C, Kelly HA, King NP, Kurtis CL, Leach AR, Manchee GR, Mason AM, Mitchell C, Patel C, Patel VK, Senger S, Shah GP, Weston HE, Whitworth C, Young RJ
Bioorg Med Chem Lett 16 3784-8 (2006)
Cited: 21 times
EuropePMC logo PMID: 16697194

Abstract

A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.

Articles - 2cji mentioned but not cited (5)

  1. Role of the active-site solvent in the thermodynamics of factor Xa ligand binding. Abel R, Young T, Farid R, Berne BJ, Friesner RA. J. Am. Chem. Soc. 130 2817-2831 (2008)
  2. CSAR benchmark exercise of 2010: selection of the protein-ligand complexes. Dunbar JB, Smith RD, Yang CY, Ung PM, Lexa KW, Khazanov NA, Stuckey JA, Wang S, Carlson HA. J Chem Inf Model 51 2036-2046 (2011)
  3. Inclusion of multiple fragment types in the site identification by ligand competitive saturation (SILCS) approach. Raman EP, Yu W, Lakkaraju SK, MacKerell AD. J Chem Inf Model 53 3384-3398 (2013)
  4. A molecular mechanics approach to modeling protein-ligand interactions: relative binding affinities in congeneric series. Rapp C, Kalyanaraman C, Schiffmiller A, Schoenbrun EL, Jacobson MP. J Chem Inf Model 51 2082-2089 (2011)
  5. Factor Xa active site substrate specificity with substrate phage display and computational molecular modeling. Hsu HJ, Tsai KC, Sun YK, Chang HJ, Huang YJ, Yu HM, Lin CH, Mao SS, Yang AS. J. Biol. Chem. 283 12343-12353 (2008)


Reviews citing this publication (1)

  1. Developments in factor Xa inhibitors for the treatment of thromboembolic disorders. Lee YK, Player MR. Med Res Rev 31 202-283 (2011)

Articles citing this publication (15)

  1. CSAR benchmark exercise of 2010: combined evaluation across all submitted scoring functions. Smith RD, Dunbar JB, Ung PM, Esposito EX, Yang CY, Wang S, Carlson HA. J Chem Inf Model 51 2115-2131 (2011)
  2. CSAR 2014: A Benchmark Exercise Using Unpublished Data from Pharma. Carlson HA, Smith RD, Damm-Ganamet KL, Stuckey JA, Ahmed A, Convery MA, Somers DO, Kranz M, Elkins PA, Cui G, Peishoff CE, Lambert MH, Dunbar JB. J Chem Inf Model 56 1063-1077 (2016)
  3. Structure- and property-based design of factor Xa inhibitors: pyrrolidin-2-ones with acyclic alanyl amides as P4 motifs. Young RJ, Campbell M, Borthwick AD, Brown D, Burns-Kurtis CL, Chan C, Convery MA, Crowe MC, Dayal S, Diallo H, Kelly HA, King NP, Kleanthous S, Mason AM, Mordaunt JE, Patel C, Pateman AJ, Senger S, Shah GP, Smith PW, Watson NS, Weston HE, Zhou P. Bioorg. Med. Chem. Lett. 16 5953-5957 (2006)
  4. Arylsulfonamides: a study of the relationship between activity and conformational preferences for a series of factor Xa inhibitors. Senger S, Convery MA, Chan C, Watson NS. Bioorg. Med. Chem. Lett. 16 5731-5735 (2006)
  5. Selective and dual action orally active inhibitors of thrombin and factor Xa. Young RJ, Brown D, Burns-Kurtis CL, Chan C, Convery MA, Hubbard JA, Kelly HA, Pateman AJ, Patikis A, Senger S, Shah GP, Toomey JR, Watson NS, Zhou P. Bioorg. Med. Chem. Lett. 17 2927-2930 (2007)
  6. Substituted thiophene-anthranilamides as potent inhibitors of human factor Xa. Kochanny MJ, Adler M, Ewing J, Griedel BD, Ho E, Karanjawala R, Lee W, Lentz D, Liang AM, Morrissey MM, Phillips GB, Post J, Sacchi KL, Sakata ST, Subramanyam B, Vergona R, Walters J, White KA, Whitlow M, Ye B, Zhao Z, Shaw KJ. Bioorg. Med. Chem. 15 2127-2146 (2007)
  7. Anthranilamide inhibitors of factor Xa. Mendel D, Marquart AL, Joseph S, Waid P, Yee YK, Tebbe AL, Ratz AM, Herron DK, Goodson T, Masters JJ, Franciskovich JB, Tinsley JM, Wiley MR, Weir LC, Kyle JA, Klimkowski VJ, Smith GF, Towner RD, Froelich LL, Buben J, Craft TJ. Bioorg. Med. Chem. Lett. 17 4832-4836 (2007)
  8. Antithrombotic potential of GW813893: a novel, orally active, active-site directed factor Xa inhibitor. Abboud MA, Needle SJ, Burns-Kurtis CL, Valocik RE, Koster PF, Amour AJ, Chan C, Brown D, Chaudry L, Zhou P, Patikis A, Patel C, Pateman AJ, Young RJ, Watson NS, Toomey JR. J. Cardiovasc. Pharmacol. 52 66-71 (2008)
  9. Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with biaryl P4 motifs. Young RJ, Borthwick AD, Brown D, Burns-Kurtis CL, Campbell M, Chan C, Charbaut M, Chung CW, Convery MA, Kelly HA, Paul King N, Kleanthous S, Mason AM, Pateman AJ, Patikis AN, Pinto IL, Pollard DR, Senger S, Shah GP, Toomey JR, Watson NS, Weston HE. Bioorg. Med. Chem. Lett. 18 23-27 (2008)
  10. Sulfonamide-related conformational effects and their importance in structure-based design. Senger S, Chan C, Convery MA, Hubbard JA, Shah GP, Watson NS, Young RJ. Bioorg. Med. Chem. Lett. 17 2931-2934 (2007)
  11. Structure and property based design of factor Xa inhibitors: biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs. Young RJ, Borthwick AD, Brown D, Burns-Kurtis CL, Campbell M, Chan C, Charbaut M, Convery MA, Diallo H, Hortense E, Irving WR, Kelly HA, King NP, Kleanthous S, Mason AM, Pateman AJ, Patikis AN, Pinto IL, Pollard DR, Senger S, Shah GP, Toomey JR, Watson NS, Weston HE, Zhou P. Bioorg. Med. Chem. Lett. 18 28-33 (2008)
  12. Sulfonamidolactam inhibitors of coagulation factor Xa. Smallheer JM, Wang S, Laws ML, Nakajima S, Hu Z, Han W, Jacobson I, Luettgen JM, Rossi KA, Rendina AR, Knabb RM, Wexler RR, Lam PY, Quan ML. Bioorg. Med. Chem. Lett. 18 2428-2433 (2008)
  13. Design, synthesis, and biological activity of piperidine diamine derivatives as factor Xa inhibitor. Mochizuki A, Nakamoto Y, Naito H, Uoto K, Ohta T. Bioorg. Med. Chem. Lett. 18 782-787 (2008)
  14. Synthesis and evaluation of dual antiplatelet activity of bispidine derivatives of N-substituted pyroglutamic acids. Misra A, Anil Kumar KS, Jain M, Bajaj K, Shandilya S, Srivastava S, Shukla P, Barthwal MK, Dikshit M, Dikshit DK. Eur J Med Chem 110 1-12 (2016)
  15. The impact of factor Xa inhibition on axial dependent arterial thrombus formation triggered by a tissue factor rich surface. Pugh N, Jarvis GE, Koch A, Sakariassen KS, Davis B, Farndale RW. J. Thromb. Thrombolysis 33 6-15 (2012)


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