Skip to main content
SpringerLink
Log in

D1927 and D2163

Novel Mercaptoamide Inhibitors of Matrix Metalloproteinases

  • Chapter
Matrix Metalloproteinase Inhibitors in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

  • 144 Accesses

Abstract

This chapter aims to provide a historical perspective of the Chiroscience matrix metalloproteinase inhibitor (MMPI) program, including the medicinal chemistry strategy which culminated in the clinical candidates D 1927 and D2163. We shall focus on the design of substrate-based inhibitors utilizing a novel zinc-binding group, and the discovery of novel MMPIs that display selectivity for the matrix metalloproteinases (MMPs) over the related metalloproteinase enzymes that mediate cellular shedding events will be reviewed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Beeley NRA, Ansell PRJ, Docherty AJP. Inhibitors of matrix metalloproteinases (MMPs). Curr Opin Ther Patents 1994; 4: 7–16.

    CAS  Google Scholar 

  2. Brown PD, Giavazzi R. Matrix metalloproteinase inhibition: a review of antitumour activity. Annals of Oncology 1995; 6: 967–974.

    PubMed  CAS  Google Scholar 

  3. Stetler-Stevenson WG. 1997. Matrix metalloprotease inhibitors, in Cancer Therapeutics: Experimental and Clinical Agents ( Teicher, B., ed), Humana, Totowa, NJ, pp. 241–261.

    Google Scholar 

  4. Gearing AJH, Beckett P, Christodoulou M, Churchill M, Clements J, Davidson AH, Drummond AH, Galloway WA, Gilbert R, Gordon JL, Leber TM, Mangan M, Miller K, Nayee P, Owen K, Patel S, Thomas W, Wells G, Wood LM, Woolley K. Processing of tumour necrosis factor-a precursor by metalloproteinases. Nature 1994; 370: 555–557.

    Article  PubMed  CAS  Google Scholar 

  5. Mousa SA. Mechanisms of angiogenesis in vascular disorders: potential therapeutic targets. Drugs of the Future 1998; 23: 51–60.

    Article  CAS  Google Scholar 

  6. Bird J, De Mello RC, Harper GP, Hunter DJ, Karran EH, Markwell, RE, Miles-Williams AJ, Rahman SS, Ward RW. Synthesis of novel N-phosphonoalkyl dipeptide inhibitors of human collagenase. J Med Chem 1994; 37: 158–169.

    Article  PubMed  CAS  Google Scholar 

  7. Porter JR, Millican TA, Morphy JR. Recent developments in matrix metalloproteinase inhibitors. Exp Opin Ther Patents 1995; 5: 1287–1296.

    Article  CAS  Google Scholar 

  8. Stams T, Spurlino JC, Smith DL, Wahl RC, Ho TF, Qoronfleh MW, Banks TM, Rubin B. Structure of human neutrophil collagenase reveals large 51’ specificity pocket. Nature Struct Biol 1994; 1: 119–123.

    Article  PubMed  CAS  Google Scholar 

  9. Wyvratt MJ, Patchett AA. Recent developments in the design of angiotensin-converting enzyme inhibitors. Med Res Rev 1985; 5: 483–531.

    Article  PubMed  CAS  Google Scholar 

  10. Baxter AD, Bird J, Bhogal R, Massil T, Minton KJ, Montana J, Owen DA. A novel series of matrix metalloproteinase inhibitors for the treatment of inflammatory disorders. BioMed Chem Lett 1997; 7: 897–902.

    Article  CAS  Google Scholar 

  11. Baxter AD, Bhogal R, Bird JB, Buckley GM, Gregory DS, Hedger PC, Manallack DT, Massil T, Minton KJ, Montana JG, Neidle S, Owen DA, Watson RJ. Mercaptoacyl matrix metalloproteinase inhibitors: the effect of substitution at the mercaptoacyl moiety. BioMed Chem Lett 1997; 7: 2765–2770.

    Article  CAS  Google Scholar 

  12. Lovejoy B, Hassell AM, Luther MA, Weigl D, Jordan SR. Crystal structures of recombinant 19kDa human fibroblast collagenase complexed to itself. Biochemistry 1994; 33 (27): 8207–8217.

    Article  PubMed  CAS  Google Scholar 

  13. Gomis-Ruth FX, Maskos K, Betz M, Bergner A, Huber R, Suzuki K, Yoshida N, Nagase H, Brew K, Bourenkov GP, Bartunik H, Bode W. Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1. Nature 1997; 389 (6646), 77–81.

    Article  PubMed  CAS  Google Scholar 

  14. Brown P (1994). Inhibitors of matrix metalloproteinases, at SCI Fine Chemicals Group Symposium, New Horizons in Anti-inflammatory Therapy. 11th May 1994, Scientific Societies Lecture Theatre, New Burlington Place, London, WI.

    Google Scholar 

  15. Eccles SA, Box GM, Court WJ, Bone EA, Thomas W, Brown PD. Control of lymphatic and hematogenous metastasis of a rat mammary carcinoma by the matrix metalloproteinase inhibitor batimastat. Cancer Research 1996; 56 (12), 2815–2822.

    PubMed  CAS  Google Scholar 

  16. Drummond AH, Beckett P, Bone EA. BB-2516: an orally bioavailable matrix metalloproteinase inhibitor with efficacy in animal cancer models. Proc Am Assoc Cancer Res 1995; 36: 100 (abstract).

    Google Scholar 

  17. Millar A, Parsons S, Primrose J, Poole C, Evans J 1996. Phase II clinical trials of marimastat. Proceedings of the 21st Congress of the European Society for Medical Oncology, Vienna, Austria.

    Google Scholar 

  18. Wojtowicz-Praga S, Torri J, Johnson M, Steen V, Marshall J, Ness E, Dickson R, Sale M, Rasmussen HS, Chiodo TA, Hawkins MJ. Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer. J. Clin. Oncology 1998; 16: 2150–2156.

    CAS  Google Scholar 

  19. Lombard MA, Wallace TL, Kubicek MF, Petzold GL, Mitchell MA, Hendges SK, Wilks JW. Synthetic matrix metalloproteinase inhibitors and tissue inhibitor of metalloproteinase (TIMP)-2, but not TIMP-1, inhibit shedding of tumor necrosis factor-a receptors in a human colon adenocarcinoma (Colo 205) cell line. Cancer Res 1998; 58: 4001–4007.

    PubMed  CAS  Google Scholar 

  20. McGeehan GM, Becherer JD, Bast RC, Boyer CM, Champion B, Connolly KM, Conway JG, Furdon P, Karp S, Kidao S, McElroy AB, Nichols J, Pryzwansky KM, Schoenen F, Sekut L, Truesdale A, Verghese M, Warner J, Ways JP. Regulation of tumour necrosis factor-a processing by a metalloproteinase inhibitor. Nature 1994; 370: 558–561.

    Article  PubMed  CAS  Google Scholar 

  21. Williams LM, Gibbons DL, Gearing A, Maini RN, Feldmann M, Brennan FM. Paradoxical effects of a synthetic metalloproteinase inhibitor that blocks both p55 and p75 TNF receptor shedding and TNF alpha processing in RA synovial membrane cell cultures. J Clin Invest 1996; 97: 2833–2841.

    Article  PubMed  CAS  Google Scholar 

  22. Tiffen P and Adger B, Tetrahedron Letters 1997; 38: 2153.

    Google Scholar 

  23. von Geldern TW, Hoffman DJ, Kester JA, Nellans HN, Dayton BD, Calzadilla SV, Marsh KC, Hernendez L, Chiou W, Dixon DB, Wu-Wong JR, Opgenorth TJ. Azole endothelin antagonists 3: Using D log Pas a tool to improve absorption J. Med. Chem. 1996; 39, 982–991.

    Article  Google Scholar 

  24. Drummond AH. Paper given at the CHI conference on ‘Protease inhibitors: new therapeutics and approaches’. Baltimore, USA, November 1996.

    Google Scholar 

Download references

Authors
  1. A. D. Baxter PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. B. Bird PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Bannister PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Bhogal PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. T. Manallack PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R. W. Watson PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D. A. Owen PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J. Montana PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J. Henshilwood PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R. C. Jackson PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Corporate V.P., Clinical Affairs, Agouron Pharmaceuticals Inc., San Diego, CA, USA

    Neil J. Clendeninn MD, PhD

  2. Department of Research Pharmacology, Agouron Pharmaceuticals Inc., San Diego, CA, USA

    Krzysztof Appelt PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2001 Springer Science+Business Media New York

About this chapter

Cite this chapter

Baxter, A.D. et al. (2001). D1927 and D2163. In: Clendeninn, N.J., Appelt, K. (eds) Matrix Metalloproteinase Inhibitors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-011-7_8

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-011-7_8

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-123-3

  • Online ISBN: 978-1-59259-011-7

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation