SAR of tertiary carbinamine derived BACE1 inhibitors: Role of aspartate ligand amine pKa in enzyme inhibition

Hemaka A. Rajapakse, Philippe G. Nantermet, Harold G. Selnick, James C. Barrow, Georgia B. McGaughey, Sanjeev Munshi, Stacey R. Lindsley, Mary Beth Young, Phung L. Ngo, M. Katherine Holloway, Ming Tain Lai, Amy S. Espeseth, Xiao Ping Shi, Dennis Colussi, Beth Pietrak, Ming Chih Crouthamel, Katherine Tugusheva, Qian Huang, Min Xu, Adam J. SimonLawrence Kuo, Daria J. Hazuda, Samuel Graham, Joseph P. Vacca

Research output: Contribution to journalArticlepeer-review


The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pKa of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Αβ production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.

Original languageEnglish (US)
Pages (from-to)1885-1889
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Issue number6
StatePublished - Mar 15 2010
Externally publishedYes


  • BACE1
  • Cell assay
  • Correlation
  • Enzyme assay
  • Tertiary carbinamine

ASJC Scopus subject areas

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


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