Methyl-substitution of an iminohydantoin spiropiperidine β-secretase (BACE-1) inhibitor has a profound effect on its potency

Melissa Egbertson; Georgia B. McGaughey; Steven M. Pitzenberger; Shaun R. Stauffer; Craig A. Coburn; Shawn J. Stachel; Wenjin Yang; James C. Barrow; Lou Anne Neilson; Melody McWherter; Debra Perlow; Bruce Fahr; Sanjeev Munshi; Timothy J. Allison; Katharine Holloway; Harold G. Selnick; Zhiqiang Yang; John Swestock; Adam J. Simon; Sethu Sankaranarayanan; Dennis Colussi; Katherine Tugusheva; Ming Tain Lai; Beth Pietrak; Shari Haugabook; Lixia Jin; I. W. Chen; Marie Holahan; Maria Stranieri-Michener; Jacquelynn J. Cook; Joseph Vacca; Samuel L. Graham

doi:10.1016/j.bmcl.2015.06.082

Methyl-substitution of an iminohydantoin spiropiperidine β-secretase (BACE-1) inhibitor has a profound effect on its potency

Melissa Egbertson, Georgia B. McGaughey, Steven M. Pitzenberger, Shaun R. Stauffer, Craig A. Coburn, Shawn J. Stachel, Wenjin Yang, James C. Barrow, Lou Anne Neilson, Melody McWherter, Debra Perlow, Bruce Fahr, Sanjeev Munshi, Timothy J. Allison, Katharine Holloway, Harold G. Selnick, Zhiqiang Yang, John Swestock, Adam J. Simon, Sethu SankaranarayananDennis Colussi, Katherine Tugusheva, Ming Tain Lai, Beth Pietrak, Shari Haugabook, Lixia Jin, I. W. Chen, Marie Holahan, Maria Stranieri-Michener, Jacquelynn J. Cook, Joseph Vacca, Samuel L. Graham

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

13 Scopus citations

Abstract

The IC₅₀ of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 μM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pK_a of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.

Original language	English (US)
Pages (from-to)	4812-4819
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	21
DOIs	https://doi.org/10.1016/j.bmcl.2015.06.082
State	Published - Nov 1 2015
Externally published	Yes

Keywords

Amyloid
Beta secretase
Magic methyl effect
Spiropiperidine

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2015.06.082

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Egbertson, M., McGaughey, G. B., Pitzenberger, S. M., Stauffer, S. R., Coburn, C. A., Stachel, S. J., Yang, W., Barrow, J. C., Neilson, L. A., McWherter, M., Perlow, D., Fahr, B., Munshi, S., Allison, T. J., Holloway, K., Selnick, H. G., Yang, Z., Swestock, J., Simon, A. J., ... Graham, S. L. (2015). Methyl-substitution of an iminohydantoin spiropiperidine β-secretase (BACE-1) inhibitor has a profound effect on its potency. Bioorganic and Medicinal Chemistry Letters, 25(21), 4812-4819. https://doi.org/10.1016/j.bmcl.2015.06.082

Egbertson, M, McGaughey, GB, Pitzenberger, SM, Stauffer, SR, Coburn, CA, Stachel, SJ, Yang, W, Barrow, JC, Neilson, LA, McWherter, M, Perlow, D, Fahr, B, Munshi, S, Allison, TJ, Holloway, K, Selnick, HG, Yang, Z, Swestock, J, Simon, AJ, Sankaranarayanan, S, Colussi, D, Tugusheva, K, Lai, MT, Pietrak, B, Haugabook, S, Jin, L, Chen, IW, Holahan, M, Stranieri-Michener, M, Cook, JJ, Vacca, J & Graham, SL 2015, 'Methyl-substitution of an iminohydantoin spiropiperidine β-secretase (BACE-1) inhibitor has a profound effect on its potency', Bioorganic and Medicinal Chemistry Letters, vol. 25, no. 21, pp. 4812-4819. https://doi.org/10.1016/j.bmcl.2015.06.082

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title = "Methyl-substitution of an iminohydantoin spiropiperidine β-secretase (BACE-1) inhibitor has a profound effect on its potency",

abstract = "The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 μM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.",

keywords = "Amyloid, Beta secretase, Magic methyl effect, Spiropiperidine",

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AU - Egbertson, Melissa

AU - McGaughey, Georgia B.

AU - Pitzenberger, Steven M.

AU - Stauffer, Shaun R.

AU - Coburn, Craig A.

AU - Stachel, Shawn J.

AU - Yang, Wenjin

AU - Barrow, James C.

AU - Neilson, Lou Anne

AU - McWherter, Melody

AU - Perlow, Debra

AU - Fahr, Bruce

AU - Munshi, Sanjeev

AU - Allison, Timothy J.

AU - Holloway, Katharine

AU - Selnick, Harold G.

AU - Yang, Zhiqiang

AU - Swestock, John

AU - Simon, Adam J.

AU - Sankaranarayanan, Sethu

AU - Colussi, Dennis

AU - Tugusheva, Katherine

AU - Lai, Ming Tain

AU - Pietrak, Beth

AU - Haugabook, Shari

AU - Jin, Lixia

AU - Chen, I. W.

AU - Holahan, Marie

AU - Stranieri-Michener, Maria

AU - Cook, Jacquelynn J.

AU - Vacca, Joseph

AU - Graham, Samuel L.

PY - 2015/11/1

Y1 - 2015/11/1

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AB - The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 μM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.

KW - Amyloid

KW - Beta secretase

KW - Magic methyl effect

KW - Spiropiperidine

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Methyl-substitution of an iminohydantoin spiropiperidine β-secretase (BACE-1) inhibitor has a profound effect on its potency

Abstract

Keywords

ASJC Scopus subject areas

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