Synthesis, characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitors

Matthew Volgraf, Lina Chan, Malcolm P. Huestis, Hans E. Purkey, Michael Burkard, Mary Geck Do, Julie Harris, Kevin W. Hunt, Xingrong Liu, Joseph P. Lyssikatos, Sumeet Rana, Allen A. Thomas, Guy P.A. Vigers, Michael Siu

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The development of 1,3,4,4a,5,10a-hexahydropyrano[3,4-b]chromene analogs as BACE1 inhibitors is described. Introduction of the spirocyclic pyranochromene scaffold yielded several advantages over previous generation cores, including increased potency, reduced efflux, and reduced CYP2D6 inhibition. Compound 13 (BACE1 IC50 = 110 nM) demonstrated a reduction in CSF Aβ in wild type rats after a single dose.

Original languageEnglish (US)
Pages (from-to)2477-2480
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number11
DOIs
StatePublished - Jun 1 2014

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Benzopyrans
Cytochrome P-450 CYP2D6
Scaffolds
Inhibitory Concentration 50
Rats

Keywords

  • Alzheimer's disease
  • BACE1 inhibitors
  • Structure-based ligand design

ASJC Scopus subject areas

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

Cite this

Synthesis, characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitors. / Volgraf, Matthew; Chan, Lina; Huestis, Malcolm P.; Purkey, Hans E.; Burkard, Michael; Geck Do, Mary; Harris, Julie; Hunt, Kevin W.; Liu, Xingrong; Lyssikatos, Joseph P.; Rana, Sumeet; Thomas, Allen A.; Vigers, Guy P.A.; Siu, Michael.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 24, No. 11, 01.06.2014, p. 2477-2480.

Research output: Contribution to journalArticle

Volgraf, M, Chan, L, Huestis, MP, Purkey, HE, Burkard, M, Geck Do, M, Harris, J, Hunt, KW, Liu, X, Lyssikatos, JP, Rana, S, Thomas, AA, Vigers, GPA & Siu, M 2014, 'Synthesis, characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 24, no. 11, pp. 2477-2480. https://doi.org/10.1016/j.bmcl.2014.04.012
Volgraf, Matthew ; Chan, Lina ; Huestis, Malcolm P. ; Purkey, Hans E. ; Burkard, Michael ; Geck Do, Mary ; Harris, Julie ; Hunt, Kevin W. ; Liu, Xingrong ; Lyssikatos, Joseph P. ; Rana, Sumeet ; Thomas, Allen A. ; Vigers, Guy P.A. ; Siu, Michael. / Synthesis, characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2014 ; Vol. 24, No. 11. pp. 2477-2480.
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