Hydroxyethylamine-based inhibitors of BACE1: P1-P3 macrocyclization can improve potency, selectivity, and cell activity

Lewis D. Pennington; Douglas A. Whittington; Michael D. Bartberger; Steven R. Jordan; Holger Monenschein; Thomas T. Nguyen; Bryant H. Yang; Qiufen M. Xue; Filisaty Vounatsos; Robert C. Wahl; Kui Chen; Stephen Wood; Martin Citron; Vinod F. Patel; Stephen A. Hitchcock; Wenge Zhong

doi:10.1016/j.bmcl.2013.05.028

Hydroxyethylamine-based inhibitors of BACE1: P₁-P₃ macrocyclization can improve potency, selectivity, and cell activity

Lewis D. Pennington, Douglas A. Whittington, Michael D. Bartberger, Steven R. Jordan, Holger Monenschein, Thomas T. Nguyen, Bryant H. Yang, Qiufen M. Xue, Filisaty Vounatsos, Robert C. Wahl, Kui Chen, Stephen Wood, Martin Citron, Vinod F. Patel, Stephen A. Hitchcock, Wenge Zhong

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

18 Scopus citations

Abstract

We describe a systematic study of how macrocyclization in the P ₁-P₃ region of hydroxyethylamine-based inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid β-peptide (Aβ)-lowering activity in HEK293T cells stably expressing APP_SW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.

Original language	English
Pages (from-to)	4459-4464
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	15
DOIs	https://doi.org/10.1016/j.bmcl.2013.05.028
State	Published - 1 Aug 2013
Externally published	Yes

Keywords

Alzheimer's disease
BACE1 inhibitor
Conformational constraint
Macrocycle
β-Secretase

Access to Document

10.1016/j.bmcl.2013.05.028

Cite this

Pennington, L. D., Whittington, D. A., Bartberger, M. D., Jordan, S. R., Monenschein, H., Nguyen, T. T., Yang, B. H., Xue, Q. M., Vounatsos, F., Wahl, R. C., Chen, K., Wood, S., Citron, M., Patel, V. F., Hitchcock, S. A., & Zhong, W. (2013). Hydroxyethylamine-based inhibitors of BACE1: P₁-P₃ macrocyclization can improve potency, selectivity, and cell activity. Bioorganic and Medicinal Chemistry Letters, 23(15), 4459-4464. https://doi.org/10.1016/j.bmcl.2013.05.028

@article{24a2d25d99a64d30b03362123b27e851,

title = "Hydroxyethylamine-based inhibitors of BACE1: P1-P3 macrocyclization can improve potency, selectivity, and cell activity",

abstract = "We describe a systematic study of how macrocyclization in the P 1-P3 region of hydroxyethylamine-based inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid β-peptide (Aβ)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.",

keywords = "Alzheimer's disease, BACE1 inhibitor, Conformational constraint, Macrocycle, β-Secretase",

author = "Pennington, {Lewis D.} and Whittington, {Douglas A.} and Bartberger, {Michael D.} and Jordan, {Steven R.} and Holger Monenschein and Nguyen, {Thomas T.} and Yang, {Bryant H.} and Xue, {Qiufen M.} and Filisaty Vounatsos and Wahl, {Robert C.} and Kui Chen and Stephen Wood and Martin Citron and Patel, {Vinod F.} and Hitchcock, {Stephen A.} and Wenge Zhong",

note = "Funding Information: We thank Vivian Li and Alexander Long (Molecular Structure and Characterization, Amgen) for providing the BACE1 protein used in the structural studies. The Advanced Light Source is supported by the U.S. Department of Energy under Contract No. DE-AC02-05CH11231.",

year = "2013",

month = aug,

day = "1",

doi = "10.1016/j.bmcl.2013.05.028",

language = "English",

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pages = "4459--4464",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

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Pennington, LD, Whittington, DA, Bartberger, MD, Jordan, SR, Monenschein, H, Nguyen, TT, Yang, BH, Xue, QM, Vounatsos, F, Wahl, RC, Chen, K, Wood, S, Citron, M, Patel, VF, Hitchcock, SA & Zhong, W 2013, 'Hydroxyethylamine-based inhibitors of BACE1: P₁-P₃ macrocyclization can improve potency, selectivity, and cell activity', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 15, pp. 4459-4464. https://doi.org/10.1016/j.bmcl.2013.05.028

TY - JOUR

T1 - Hydroxyethylamine-based inhibitors of BACE1

T2 - P1-P3 macrocyclization can improve potency, selectivity, and cell activity

AU - Pennington, Lewis D.

AU - Whittington, Douglas A.

AU - Bartberger, Michael D.

AU - Jordan, Steven R.

AU - Monenschein, Holger

AU - Nguyen, Thomas T.

AU - Yang, Bryant H.

AU - Xue, Qiufen M.

AU - Vounatsos, Filisaty

AU - Wahl, Robert C.

AU - Chen, Kui

AU - Wood, Stephen

AU - Citron, Martin

AU - Patel, Vinod F.

AU - Hitchcock, Stephen A.

AU - Zhong, Wenge

N1 - Funding Information: We thank Vivian Li and Alexander Long (Molecular Structure and Characterization, Amgen) for providing the BACE1 protein used in the structural studies. The Advanced Light Source is supported by the U.S. Department of Energy under Contract No. DE-AC02-05CH11231.

PY - 2013/8/1

Y1 - 2013/8/1

N2 - We describe a systematic study of how macrocyclization in the P 1-P3 region of hydroxyethylamine-based inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid β-peptide (Aβ)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.

AB - We describe a systematic study of how macrocyclization in the P 1-P3 region of hydroxyethylamine-based inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid β-peptide (Aβ)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.

KW - Alzheimer's disease

KW - BACE1 inhibitor

KW - Conformational constraint

KW - Macrocycle

KW - β-Secretase

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DO - 10.1016/j.bmcl.2013.05.028

M3 - Article

C2 - 23769639

AN - SCOPUS:84879685323

SN - 0960-894X

VL - 23

SP - 4459

EP - 4464

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 15