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 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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)1788-1792
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume17
Issue number6
DOIs
StatePublished - Mar 15 2007
Externally publishedYes

Fingerprint

Amyloid Precursor Protein Secretases
Conformations
Molecular Weight
Molecular weight
P-Glycoprotein
Amines
Assays
isonicotinamide
cyclopropane

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Stauffer, S. R., Stanton, M. G., Gregro, A. R., Steinbeiser, M. A., Shaffer, J. R., Nantermet, P. G., ... 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

Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation. / Stauffer, Shaun R.; Stanton, Matthew G.; Gregro, Alison R.; Steinbeiser, Melissa A.; Shaffer, Jennifer R.; Nantermet, Philippe G.; Barrow, James; Rittle, Kenneth E.; Collusi, Dennis; Espeseth, Amy S.; Lai, Ming Tain; Pietrak, Beth L.; Holloway, M. Katharine; McGaughey, Georgia B.; Munshi, Sanjeev K.; Hochman, Jerome H.; Simon, Adam J.; Selnick, Harold G.; Graham, Samuel L.; Vacca, Joseph P.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 17, No. 6, 15.03.2007, p. 1788-1792.

Research output: Contribution to journalArticle

Stauffer, SR, Stanton, MG, Gregro, AR, Steinbeiser, MA, Shaffer, JR, Nantermet, PG, Barrow, J, 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
Stauffer, Shaun R. ; Stanton, Matthew G. ; Gregro, Alison R. ; Steinbeiser, Melissa A. ; Shaffer, Jennifer R. ; Nantermet, Philippe G. ; Barrow, James ; Rittle, Kenneth E. ; Collusi, Dennis ; Espeseth, Amy S. ; Lai, Ming Tain ; Pietrak, Beth L. ; Holloway, M. Katharine ; McGaughey, Georgia B. ; Munshi, Sanjeev K. ; Hochman, Jerome H. ; Simon, Adam J. ; Selnick, Harold G. ; Graham, Samuel L. ; Vacca, Joseph P. / Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation. In: Bioorganic and Medicinal Chemistry Letters. 2007 ; Vol. 17, No. 6. pp. 1788-1792.
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