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

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

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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

Cite this

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