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

James C. Barrow; Shaun R. Stauffer; Kenneth E. Rittle; Phung L. Ngo; Zhi Qiang 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; Beth Pietrak; Paul Zuck; Dorothy A. Levorse; Daria Hazuda; Joseph P. Vacca

doi:10.1021/jm800914n

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

James C. Barrow, Shaun R. Stauffer, Kenneth E. Rittle, Phung L. Ngo, Zhi Qiang 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 WolfeBeth Pietrak, Paul Zuck, Dorothy A. Levorse, Daria Hazuda, Joseph P. Vacca

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

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 language	English (US)
Pages (from-to)	6259-6262
Number of pages	4
Journal	Journal of medicinal chemistry
Volume	51
Issue number	20
DOIs	https://doi.org/10.1021/jm800914n
State	Published - Oct 23 2008
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Barrow, J. C., Stauffer, S. R., Rittle, K. E., Ngo, P. L., Yang, Z. Q., Selnick, H. G., Graham, S. L., Munshi, S., McGaughey, G. B., Holloway, M. K., Simon, A. J., Price, E. A., Sankaranarayanan, S., Colussi, D., Tugusheva, K., Lai, M. T., Espeseth, A. S., Xu, M., Huang, Q., ... 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

Barrow, JC, Stauffer, SR, Rittle, KE, Ngo, PL, Yang, ZQ, 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

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title = "Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of β-secretase",

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.",

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

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AU - Barrow, James C.

AU - Stauffer, Shaun R.

AU - Rittle, Kenneth E.

AU - Ngo, Phung L.

AU - Yang, Zhi Qiang

AU - Selnick, Harold G.

AU - Graham, Samuel L.

AU - Munshi, Sanjeev

AU - McGaughey, Georgia B.

AU - Holloway, M. Katharine

AU - Simon, Adam J.

AU - Price, Eric A.

AU - Sankaranarayanan, Sethu

AU - Colussi, Dennis

AU - Tugusheva, Katherine

AU - Lai, Ming Tain

AU - Espeseth, Amy S.

AU - Xu, Min

AU - Huang, Qian

AU - Wolfe, Abigail

AU - Pietrak, Beth

AU - Zuck, Paul

AU - Levorse, Dorothy A.

AU - Hazuda, Daria

AU - Vacca, Joseph P.

PY - 2008/10/23

Y1 - 2008/10/23

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AB - 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.

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

Abstract

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