Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of β-secretase

James Barrow, Shaun R. Stauffer, Kenneth E. Rittle, Phung L. Ngo, ZhiQiang Yang, Harold G. Selnick, Samuel L. Graham, Sanjeev Munshi, Georgia B. McGaughey, M. Katharine Holloway, Adam J. Simon, Eric A. Price, Sethu Sankaranarayanan, Dennis Colussi, Katherine Tugusheva, Ming Tain Lai, Amy S. Espeseth, Min Xu, Qian Huang, Abigail Wolfe & 5 others Beth Pietrak, Paul Zuck, Dorothy A. Levorse, Daria Hazuda, Joseph P. Vacca

Research output: Contribution to journalArticle

Abstract

A high-throughput screen at 100 μM inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging water molecules. Using the crystal structure as a guide, potent compounds with good brain penetration were designed.

Original languageEnglish (US)
Pages (from-to)6259-6262
Number of pages4
JournalJournal of Medicinal Chemistry
Volume51
Issue number20
DOIs
StatePublished - Oct 23 2008
Externally publishedYes

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Aspartic Acid Proteases
Amyloid Precursor Protein Secretases
Protease Inhibitors
Aspartic Acid
X-Rays
Water
Brain
Enzymes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Barrow, J., Stauffer, S. R., Rittle, K. E., Ngo, P. L., Yang, Z., Selnick, H. G., ... Vacca, J. P. (2008). Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of β-secretase. Journal of Medicinal Chemistry, 51(20), 6259-6262. https://doi.org/10.1021/jm800914n

Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of β-secretase. / Barrow, James; Stauffer, Shaun R.; Rittle, Kenneth E.; Ngo, Phung L.; Yang, ZhiQiang; Selnick, Harold G.; Graham, Samuel L.; Munshi, Sanjeev; McGaughey, Georgia B.; Holloway, M. Katharine; Simon, Adam J.; Price, Eric A.; Sankaranarayanan, Sethu; Colussi, Dennis; Tugusheva, Katherine; Lai, Ming Tain; Espeseth, Amy S.; Xu, Min; Huang, Qian; Wolfe, Abigail; Pietrak, Beth; Zuck, Paul; Levorse, Dorothy A.; Hazuda, Daria; Vacca, Joseph P.

In: Journal of Medicinal Chemistry, Vol. 51, No. 20, 23.10.2008, p. 6259-6262.

Research output: Contribution to journalArticle

Barrow, J, Stauffer, SR, Rittle, KE, Ngo, PL, Yang, Z, Selnick, HG, Graham, SL, Munshi, S, McGaughey, GB, Holloway, MK, Simon, AJ, Price, EA, Sankaranarayanan, S, Colussi, D, Tugusheva, K, Lai, MT, Espeseth, AS, Xu, M, Huang, Q, Wolfe, A, Pietrak, B, Zuck, P, Levorse, DA, Hazuda, D & Vacca, JP 2008, 'Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of β-secretase', Journal of Medicinal Chemistry, vol. 51, no. 20, pp. 6259-6262. https://doi.org/10.1021/jm800914n
Barrow, James ; Stauffer, Shaun R. ; Rittle, Kenneth E. ; Ngo, Phung L. ; Yang, ZhiQiang ; Selnick, Harold G. ; Graham, Samuel L. ; Munshi, Sanjeev ; McGaughey, Georgia B. ; Holloway, M. Katharine ; Simon, Adam J. ; Price, Eric A. ; Sankaranarayanan, Sethu ; Colussi, Dennis ; Tugusheva, Katherine ; Lai, Ming Tain ; Espeseth, Amy S. ; Xu, Min ; Huang, Qian ; Wolfe, Abigail ; Pietrak, Beth ; Zuck, Paul ; Levorse, Dorothy A. ; Hazuda, Daria ; Vacca, Joseph P. / Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of β-secretase. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 20. pp. 6259-6262.
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