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Structure-based design and synthesis of pyrazinones containing novel P1 'side pocket' moieties as inhibitors of TF/VIIa.

Schweitzer BA, Neumann WL, Rahman HK, Kusturin CL, Sample KR, Poda GI, Kurumbail RG, Stevens AM, Stegeman RA, Stallings WC, South MS
Bioorg Med Chem Lett 15 3006-11 (2005)
Cited: 9 times
EuropePMC logo PMID: 15913999

Abstract

We describe the structure-based design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors contain substituents meta to the P(1) amidine designed to explore additional interactions with the VIIa residues in the so-called 'S(1) side pocket'. A crystal structure of the designed inhibitors demonstrates the ability of the P(1) side pocket moiety to engage Lys192 and main chain of Gly216 via hydrogen bond interactions, thus, providing additional possibility for chemical modification to improve selectivity and/or physical properties of inhibitors.

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Reviews citing this publication (1)

  1. Inhibitors of Factor VIIa/tissue factor. Shirk RA, Vlasuk GP. Arterioscler. Thromb. Vasc. Biol. 27 1895-1900 (2007)

Articles citing this publication (6)

  1. Factor VIIa inhibitors: target hopping in the serine protease family using X-ray structure determination. Shiraishi T, Kadono S, Haramura M, Kodama H, Ono Y, Iikura H, Esaki T, Koga T, Hattori K, Watanabe Y, Sakamoto A, Yoshihashi K, Kitazawa T, Esaki K, Ohta M, Sato H, Kozono T. Bioorg. Med. Chem. Lett. 18 4533-4537 (2008)
  2. The discovery of fluoropyridine-based inhibitors of the factor VIIa/TF complex--Part 2. Kohrt JT, Filipski KJ, Cody WL, Cai C, Dudley DA, Van Huis CA, Willardsen JA, Narasimhan LS, Zhang E, Rapundalo ST, Saiya-Cork K, Leadley RJ, Edmunds JJ. Bioorg. Med. Chem. Lett. 16 1060-1064 (2006)
  3. The discovery of fluoropyridine-based inhibitors of the Factor VIIa/TF complex. Kohrt JT, Filipski KJ, Cody WL, Cai C, Dudley DA, Van Huis CA, Willardsen JA, Rapundalo ST, Saiya-Cork K, Leadley RJ, Narasimhan L, Zhang E, Whitlow M, Adler M, McLean K, Chou YL, McKnight C, Arnaiz DO, Shaw KJ, Light DR, Edmunds JJ. Bioorg. Med. Chem. Lett. 15 4752-4756 (2005)
  4. Design, parallel synthesis, and crystal structures of biphenyl antithrombotics as selective inhibitors of tissue factor FVIIa complex. Part 1: Exploration of S2 pocket pharmacophores. Kotian PL, Krishnan R, Rowland S, El-Kattan Y, Saini SK, Upshaw R, Bantia S, Arnold S, Babu YS, Chand P. Bioorg. Med. Chem. 17 3934-3958 (2009)
  5. On-bead combinatorial techniques for the identification of selective aldose reductase inhibitors. Robins LI, Dixon SM, Wilson DK, Kurth MJ. Bioorg. Med. Chem. 14 7728-7735 (2006)
  6. Design and synthesis of peptidomimetic factor VIIa inhibitors. Shiraishi T, Kadono S, Haramura M, Kodama H, Ono Y, Iikura H, Esaki T, Koga T, Hattori K, Watanabe Y, Sakamoto A, Yoshihashi K, Kitazawa T, Esaki K, Ohta M, Sato H, Kozono T. Chem. Pharm. Bull. 58 38-44 (2010)


Related citations provided by authors (2)

  1. Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex.. South MS, Case BL, Wood RS, Jones DE, Hayes MJ, Girard TJ, Lachance RM, Nicholson NS, Clare M, Stevens AM, Stegeman RA, Stallings WC, Kurumbail RG, Parlow JJ Bioorg Med Chem Lett 13 2319-25 (2003)
  2. Polymer-assisted solution-phase library synthesis and crystal structure of alpha-ketothiazoles as tissue factor VIIa inhibitors.. Parlow JJ, Dice TA, Lachance RM, Girard TJ, Stevens AM, Stegeman RA, Stallings WC, Kurumbail RG, South MS J Med Chem 46 4043-9 (2003)

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