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 journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)4812-4819
Number of pages8
JournalBioorganic and Medicinal Chemistry Letters
Issue number21
StatePublished - Nov 1 2015
Externally publishedYes


  • 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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