8-tetrahydropyran-2-yl chromans: Highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors

Allen A. Thomas; Kevin W. Hunt; Brad Newhouse; Ryan J. Watts; Xingrong Liu; Guy Vigers; Darin Smith; Susan P. Rhodes; Karin D. Brown; Jennifer N. Otten; Michael Burkard; April A. Cox; Mary K. Geck Do; Darrin Dutcher; Sumeet Rana; Robert K. Delisle; Kelly Regal; Albion D. Wright; Robert Groneberg; Jiangpeng Liao; Kimberly Scearce-Levie; Michael Siu; Hans E. Purkey; Joseph P. Lyssikatos

doi:10.1021/jm5015132

8-tetrahydropyran-2-yl chromans: Highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors

Allen A. Thomas, Kevin W. Hunt, Brad Newhouse, Ryan J. Watts, Xingrong Liu, Guy Vigers, Darin Smith, Susan P. Rhodes, Karin D. Brown, Jennifer N. Otten, Michael Burkard, April A. Cox, Mary K. Geck Do, Darrin Dutcher, Sumeet Rana, Robert K. Delisle, Kelly Regal, Albion D. Wright, Robert Groneberg, Jiangpeng LiaoKimberly Scearce-Levie, Michael Siu, Hans E. Purkey, Joseph P. Lyssikatos

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16 Scopus citations

Abstract

A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2′ and P3 moieties were explored. A conformationally restricted P2′ methyl group provided inhibitors with excellent cell potency (37-137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF Aβ_1-40 at 60 mg/kg (PO).

Original language	English (US)
Pages (from-to)	10112-10129
Number of pages	18
Journal	Journal of Medicinal Chemistry
Volume	57
Issue number	23
DOIs	https://doi.org/10.1021/jm5015132
State	Published - Dec 11 2014

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Thomas, A. A., Hunt, K. W., Newhouse, B., Watts, R. J., Liu, X., Vigers, G., Smith, D., Rhodes, S. P., Brown, K. D., Otten, J. N., Burkard, M., Cox, A. A., Geck Do, M. K., Dutcher, D., Rana, S., Delisle, R. K., Regal, K., Wright, A. D., Groneberg, R., ... Lyssikatos, J. P. (2014). 8-tetrahydropyran-2-yl chromans: Highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors. Journal of Medicinal Chemistry, 57(23), 10112-10129. https://doi.org/10.1021/jm5015132

Thomas, AA, Hunt, KW, Newhouse, B, Watts, RJ, Liu, X, Vigers, G, Smith, D, Rhodes, SP, Brown, KD, Otten, JN, Burkard, M, Cox, AA, Geck Do, MK, Dutcher, D, Rana, S, Delisle, RK, Regal, K, Wright, AD, Groneberg, R, Liao, J, Scearce-Levie, K, Siu, M, Purkey, HE & Lyssikatos, JP 2014, '8-tetrahydropyran-2-yl chromans: Highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors', Journal of Medicinal Chemistry, vol. 57, no. 23, pp. 10112-10129. https://doi.org/10.1021/jm5015132

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title = "8-tetrahydropyran-2-yl chromans: Highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors",

abstract = "A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2′ and P3 moieties were explored. A conformationally restricted P2′ methyl group provided inhibitors with excellent cell potency (37-137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF Aβ1-40 at 60 mg/kg (PO).",

author = "Thomas, {Allen A.} and Hunt, {Kevin W.} and Brad Newhouse and Watts, {Ryan J.} and Xingrong Liu and Guy Vigers and Darin Smith and Rhodes, {Susan P.} and Brown, {Karin D.} and Otten, {Jennifer N.} and Michael Burkard and Cox, {April A.} and {Geck Do}, {Mary K.} and Darrin Dutcher and Sumeet Rana and Delisle, {Robert K.} and Kelly Regal and Wright, {Albion D.} and Robert Groneberg and Jiangpeng Liao and Kimberly Scearce-Levie and Michael Siu and Purkey, {Hans E.} and Lyssikatos, {Joseph P.}",

note = "Publisher Copyright: {\textcopyright} 2014 American Chemical Society.",

year = "2014",

month = dec,

day = "11",

doi = "10.1021/jm5015132",

language = "English (US)",

volume = "57",

pages = "10112--10129",

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AU - Hunt, Kevin W.

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AU - Watts, Ryan J.

AU - Liu, Xingrong

AU - Vigers, Guy

AU - Smith, Darin

AU - Rhodes, Susan P.

AU - Brown, Karin D.

AU - Otten, Jennifer N.

AU - Burkard, Michael

AU - Cox, April A.

AU - Geck Do, Mary K.

AU - Dutcher, Darrin

AU - Rana, Sumeet

AU - Delisle, Robert K.

AU - Regal, Kelly

AU - Wright, Albion D.

AU - Groneberg, Robert

AU - Liao, Jiangpeng

AU - Scearce-Levie, Kimberly

AU - Siu, Michael

AU - Purkey, Hans E.

AU - Lyssikatos, Joseph P.

PY - 2014/12/11

Y1 - 2014/12/11

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AB - A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2′ and P3 moieties were explored. A conformationally restricted P2′ methyl group provided inhibitors with excellent cell potency (37-137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF Aβ1-40 at 60 mg/kg (PO).

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8-tetrahydropyran-2-yl chromans: Highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors

Abstract

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