A potent and orally efficacious, hydroxyethylamine-based inhibitor of β-Secretase

Matthew R. Kaller; Scott S. Harried; Brian Albrecht; Patricia Amarante; Safura Babu-Khan; Michael D. Bartberger; James Brown; Ryan Brown; Kui Chen; Yuan Cheng; Martin Citron; Michael D. Croghan; Russell Graceffa; Dean Hickman; Ted Judd; Chuck Kriemen; Daniel La; Vivian Li; Patricia Lopez; Yi Luo; Craig Masse; Holger Monenschein; Thomas Nguyen; Lewis D. Pennington; Tisha San Miguel; E. Allen Sickmier; Robert C. Wahl; Matthew M. Weiss; Paul H. Wen; Toni Williamson; Stephen Wood; May Xue; Bryant Yang; Jianhua Zhang; Vinod Patel; Wenge Zhong; Stephen Hitchcock

doi:10.1021/ml3000148

A potent and orally efficacious, hydroxyethylamine-based inhibitor of β-Secretase

Matthew R. Kaller
, Scott S. Harried
, Brian Albrecht
, Patricia Amarante
, Safura Babu-Khan
, Michael D. Bartberger
, James Brown
, Ryan Brown
, Kui Chen
, Yuan Cheng
, Martin Citron
, Michael D. Croghan
, Russell Graceffa
, Dean Hickman
, Ted Judd
, Chuck Kriemen
, Daniel La
, Vivian Li
, Patricia Lopez
, Yi Luo

Craig Masse, Holger Monenschein, Thomas Nguyen, Lewis D. Pennington, Tisha San Miguel, E. Allen Sickmier, Robert C. Wahl, Matthew M. Weiss, Paul H. Wen, Toni Williamson, Stephen Wood, May Xue, Bryant Yang, Jianhua Zhang, Vinod Patel, Wenge Zhong, Stephen Hitchcock

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

β-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as 1 with low nanomolar potency against β-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce Aβ₄₀ levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 as a novel, potent, and orally efficacious BACE inhibitor.

Original language	English
Pages (from-to)	886-891
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	3
Issue number	11
DOIs	https://doi.org/10.1021/ml3000148
State	Published - 8 Nov 2012
Externally published	Yes

Keywords

Alzheimer's disease (AD)
hydroxyethylamine (HEA) isostere
β amyloid precursor protein cleaving enzyme (BACE)

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10.1021/ml3000148

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Kaller, M. R., Harried, S. S., Albrecht, B., Amarante, P., Babu-Khan, S., Bartberger, M. D., Brown, J., Brown, R., Chen, K., Cheng, Y., Citron, M., Croghan, M. D., Graceffa, R., Hickman, D., Judd, T., Kriemen, C., La, D., Li, V., Lopez, P., ... Hitchcock, S. (2012). A potent and orally efficacious, hydroxyethylamine-based inhibitor of β-Secretase. ACS Medicinal Chemistry Letters, 3(11), 886-891. https://doi.org/10.1021/ml3000148

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title = "A potent and orally efficacious, hydroxyethylamine-based inhibitor of β-Secretase",

abstract = "β-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as 1 with low nanomolar potency against β-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce Aβ40 levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 as a novel, potent, and orally efficacious BACE inhibitor.",

keywords = "Alzheimer's disease (AD), hydroxyethylamine (HEA) isostere, β amyloid precursor protein cleaving enzyme (BACE)",

author = "Kaller, \{Matthew R.\} and Harried, \{Scott S.\} and Brian Albrecht and Patricia Amarante and Safura Babu-Khan and Bartberger, \{Michael D.\} and James Brown and Ryan Brown and Kui Chen and Yuan Cheng and Martin Citron and Croghan, \{Michael D.\} and Russell Graceffa and Dean Hickman and Ted Judd and Chuck Kriemen and Daniel La and Vivian Li and Patricia Lopez and Yi Luo and Craig Masse and Holger Monenschein and Thomas Nguyen and Pennington, \{Lewis D.\} and Miguel, \{Tisha San\} and Sickmier, \{E. Allen\} and Wahl, \{Robert C.\} and Weiss, \{Matthew M.\} and Wen, \{Paul H.\} and Toni Williamson and Stephen Wood and May Xue and Bryant Yang and Jianhua Zhang and Vinod Patel and Wenge Zhong and Stephen Hitchcock",

year = "2012",

month = nov,

day = "8",

doi = "10.1021/ml3000148",

language = "English",

volume = "3",

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journal = "ACS Medicinal Chemistry Letters",

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Kaller, MR, Harried, SS, Albrecht, B, Amarante, P, Babu-Khan, S, Bartberger, MD, Brown, J, Brown, R, Chen, K, Cheng, Y, Citron, M, Croghan, MD, Graceffa, R, Hickman, D, Judd, T, Kriemen, C, La, D, Li, V, Lopez, P, Luo, Y, Masse, C, Monenschein, H, Nguyen, T, Pennington, LD, Miguel, TS, Sickmier, EA, Wahl, RC, Weiss, MM, Wen, PH, Williamson, T, Wood, S, Xue, M, Yang, B, Zhang, J, Patel, V, Zhong, W & Hitchcock, S 2012, 'A potent and orally efficacious, hydroxyethylamine-based inhibitor of β-Secretase', ACS Medicinal Chemistry Letters, vol. 3, no. 11, pp. 886-891. https://doi.org/10.1021/ml3000148

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AU - Kaller, Matthew R.

AU - Harried, Scott S.

AU - Albrecht, Brian

AU - Amarante, Patricia

AU - Babu-Khan, Safura

AU - Bartberger, Michael D.

AU - Brown, James

AU - Brown, Ryan

AU - Chen, Kui

AU - Cheng, Yuan

AU - Citron, Martin

AU - Croghan, Michael D.

AU - Graceffa, Russell

AU - Hickman, Dean

AU - Judd, Ted

AU - Kriemen, Chuck

AU - La, Daniel

AU - Li, Vivian

AU - Lopez, Patricia

AU - Luo, Yi

AU - Masse, Craig

AU - Monenschein, Holger

AU - Nguyen, Thomas

AU - Pennington, Lewis D.

AU - Miguel, Tisha San

AU - Sickmier, E. Allen

AU - Wahl, Robert C.

AU - Weiss, Matthew M.

AU - Wen, Paul H.

AU - Williamson, Toni

AU - Wood, Stephen

AU - Xue, May

AU - Yang, Bryant

AU - Zhang, Jianhua

AU - Patel, Vinod

AU - Zhong, Wenge

AU - Hitchcock, Stephen

PY - 2012/11/8

Y1 - 2012/11/8

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AB - β-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as 1 with low nanomolar potency against β-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce Aβ40 levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 as a novel, potent, and orally efficacious BACE inhibitor.

KW - Alzheimer's disease (AD)

KW - hydroxyethylamine (HEA) isostere

KW - β amyloid precursor protein cleaving enzyme (BACE)

UR - https://www.scopus.com/pages/publications/84867590209

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VL - 3

SP - 886

EP - 891

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 11

ER -

A potent and orally efficacious, hydroxyethylamine-based inhibitor of β-Secretase

Abstract

Keywords

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