Evolution of tertiary carbinamine BACE-1 inhibitors: Aβ reduction in rhesus CSF upon oral dosing

Philippe G. Nantermet, Hemaka A. Rajapakse, Mathew G. Stanton, Shaun R. Stauffer, James C. Barrow, Allison R. Gregro, Keith P. Moore, Melissa A. Steinbeiser, John Swestock, Harold G. Selnick, Samuel L. Graham, Georgia B. McGaughey, Dennis Colussi, Ming Tain Lai, Sethu Sankaranarayanan, Adam J. Simon, Sanjeev Munshi, Jacquelynn J. Cook, Marie A. Holahan, Maria S. MichenerJoseph P. Vacca

Research output: Contribution to journalArticle

Abstract

Incorporation of an isonicotinic core containing a P3 methylcyclopropyl group into our previously reported ox-adiazolyl tertiary carbinamine based BACE-1 inhibitors has led to the identification of the exquisitely potent inhibitor 6, which displays good permeability and low susceptibility to the P-gp efflux pump. Upon co-dosing with CYP 3A4 inhibitor ritonavir, tertiary carbinamine 6 was found to be orally bioavailable. Following twice daily oral administration to monkeys, it was shown to penetrate the CNS and lower Aβ42 levels in the CSF by >40% over the course of a 3 day experiment. Further structural improvements aimed at optimization of pharmacokinetics and brain penetration will be the subject of future work, as will studies of the impact of central BACE-1 inhibitor-mediated Aβ42 lowering on cognition.

Original languageEnglish (US)
Pages (from-to)37-40
Number of pages4
JournalChemMedChem
Volume4
Issue number1
DOIs
StatePublished - Jan 12 2009
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Aβ reduction
  • BACE-1
  • Inhibitors
  • β-secretase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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  • Cite this

    Nantermet, P. G., Rajapakse, H. A., Stanton, M. G., Stauffer, S. R., Barrow, J. C., Gregro, A. R., Moore, K. P., Steinbeiser, M. A., Swestock, J., Selnick, H. G., Graham, S. L., McGaughey, G. B., Colussi, D., Lai, M. T., Sankaranarayanan, S., Simon, A. J., Munshi, S., Cook, J. J., Holahan, M. A., ... Vacca, J. P. (2009). Evolution of tertiary carbinamine BACE-1 inhibitors: Aβ reduction in rhesus CSF upon oral dosing. ChemMedChem, 4(1), 37-40. https://doi.org/10.1002/cmdc.200800308