Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation

Shaun R. Stauffer; Matthew G. Stanton; Alison R. Gregro; Melissa A. Steinbeiser; Jennifer R. Shaffer; Philippe G. Nantermet; James C. Barrow; Kenneth E. Rittle; Dennis Collusi; Amy S. Espeseth; Ming Tain Lai; Beth L. Pietrak; M. Katharine Holloway; Georgia B. McGaughey; Sanjeev K. Munshi; Jerome H. Hochman; Adam J. Simon; Harold G. Selnick; Samuel L. Graham; Joseph P. Vacca

doi:10.1016/j.bmcl.2006.12.051

Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation

Shaun R. Stauffer, Matthew G. Stanton, Alison R. Gregro, Melissa A. Steinbeiser, Jennifer R. Shaffer, Philippe G. Nantermet, James C. Barrow, Kenneth E. Rittle, Dennis Collusi, Amy S. Espeseth, Ming Tain Lai, Beth L. Pietrak, M. Katharine Holloway, Georgia B. McGaughey, Sanjeev K. Munshi, Jerome H. Hochman, Adam J. Simon, Harold G. Selnick, Samuel L. Graham, Joseph P. Vacca

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59 Scopus citations

Abstract

A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P₃ which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux.

Original language	English (US)
Pages (from-to)	1788-1792
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	17
Issue number	6
DOIs	https://doi.org/10.1016/j.bmcl.2006.12.051
State	Published - Mar 15 2007
Externally published	Yes

Keywords

2,6-Diamino-isonicotinamide
Alzheimer's disease
BACE-1 inhibitors

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.2006.12.051

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Stauffer, S. R., Stanton, M. G., Gregro, A. R., Steinbeiser, M. A., Shaffer, J. R., Nantermet, P. G., Barrow, J. C., Rittle, K. E., Collusi, D., Espeseth, A. S., Lai, M. T., Pietrak, B. L., Holloway, M. K., McGaughey, G. B., Munshi, S. K., Hochman, J. H., Simon, A. J., Selnick, H. G., Graham, S. L., & Vacca, J. P. (2007). Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation. Bioorganic and Medicinal Chemistry Letters, 17(6), 1788-1792. https://doi.org/10.1016/j.bmcl.2006.12.051

Stauffer, SR, Stanton, MG, Gregro, AR, Steinbeiser, MA, Shaffer, JR, Nantermet, PG, Barrow, JC, Rittle, KE, Collusi, D, Espeseth, AS, Lai, MT, Pietrak, BL, Holloway, MK, McGaughey, GB, Munshi, SK, Hochman, JH, Simon, AJ, Selnick, HG, Graham, SL & Vacca, JP 2007, 'Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation', Bioorganic and Medicinal Chemistry Letters, vol. 17, no. 6, pp. 1788-1792. https://doi.org/10.1016/j.bmcl.2006.12.051

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title = "Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation",

abstract = "A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P3 which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux.",

keywords = "2,6-Diamino-isonicotinamide, Alzheimer's disease, BACE-1 inhibitors",

author = "Stauffer, {Shaun R.} and Stanton, {Matthew G.} and Gregro, {Alison R.} and Steinbeiser, {Melissa A.} and Shaffer, {Jennifer R.} and Nantermet, {Philippe G.} and Barrow, {James C.} and Rittle, {Kenneth E.} and Dennis Collusi and Espeseth, {Amy S.} and Lai, {Ming Tain} and Pietrak, {Beth L.} and Holloway, {M. Katharine} and McGaughey, {Georgia B.} and Munshi, {Sanjeev K.} and Hochman, {Jerome H.} and Simon, {Adam J.} and Selnick, {Harold G.} and Graham, {Samuel L.} and Vacca, {Joseph P.}",

year = "2007",

month = mar,

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doi = "10.1016/j.bmcl.2006.12.051",

language = "English (US)",

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pages = "1788--1792",

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AU - Stauffer, Shaun R.

AU - Stanton, Matthew G.

AU - Gregro, Alison R.

AU - Steinbeiser, Melissa A.

AU - Shaffer, Jennifer R.

AU - Nantermet, Philippe G.

AU - Barrow, James C.

AU - Rittle, Kenneth E.

AU - Collusi, Dennis

AU - Espeseth, Amy S.

AU - Lai, Ming Tain

AU - Pietrak, Beth L.

AU - Holloway, M. Katharine

AU - McGaughey, Georgia B.

AU - Munshi, Sanjeev K.

AU - Hochman, Jerome H.

AU - Simon, Adam J.

AU - Selnick, Harold G.

AU - Graham, Samuel L.

AU - Vacca, Joseph P.

PY - 2007/3/15

Y1 - 2007/3/15

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AB - A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P3 which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux.

KW - 2,6-Diamino-isonicotinamide

KW - Alzheimer's disease

KW - BACE-1 inhibitors

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 6

ER -

Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation

Abstract

Keywords

ASJC Scopus subject areas

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