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

doi:10.1016/j.bmcl.2014.04.012

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 journal › Article › peer-review

12 Scopus citations

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 language	English (US)
Pages (from-to)	2477-2480
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	11
DOIs	https://doi.org/10.1016/j.bmcl.2014.04.012
State	Published - Jun 1 2014
Externally published	Yes

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

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10.1016/j.bmcl.2014.04.012

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Volgraf, M., Chan, L., Huestis, M. P., Purkey, H. E., Burkard, M., Geck Do, M., Harris, J., Hunt, K. W., Liu, X., Lyssikatos, J. P., Rana, S., Thomas, A. A., Vigers, G. P. A., & Siu, M. (2014). Synthesis, characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitors. Bioorganic and Medicinal Chemistry Letters, 24(11), 2477-2480. https://doi.org/10.1016/j.bmcl.2014.04.012

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

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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.",

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AU - Volgraf, Matthew

AU - Chan, Lina

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AU - Purkey, Hans E.

AU - Burkard, Michael

AU - Geck Do, Mary

AU - Harris, Julie

AU - Hunt, Kevin W.

AU - Liu, Xingrong

AU - Lyssikatos, Joseph P.

AU - Rana, Sumeet

AU - Thomas, Allen A.

AU - Vigers, Guy P.A.

AU - Siu, Michael

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

Abstract

Keywords

ASJC Scopus subject areas

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