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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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).

Original languageEnglish (US)
Pages (from-to)10112-10129
Number of pages18
JournalJournal of Medicinal Chemistry
Volume57
Issue number23
DOIs
StatePublished - Dec 11 2014

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Chromans
Cathepsin D
Amyloid beta-Protein Precursor
Enzyme Inhibitors
Guanidines
Benzopyrans
Enzymes
Permeability

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

8-tetrahydropyran-2-yl chromans : Highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors. / Thomas, Allen A; Hunt, Kevin W.; Newhouse, Brad; Watts, Ryan J.; Liu, Xingrong; Vigers, Guy; Smith, Darin; Rhodes, Susan P.; Brown, Karin D.; Otten, Jennifer N.; Burkard, Michael; Cox, April A.; Geck Do, Mary K.; Dutcher, Darrin; Rana, Sumeet; Delisle, Robert K.; Regal, Kelly; Wright, Albion D.; Groneberg, Robert; Liao, Jiangpeng; Scearce-Levie, Kimberly; Siu, Michael; Purkey, Hans E.; Lyssikatos, Joseph P.

In: Journal of Medicinal Chemistry, Vol. 57, No. 23, 11.12.2014, p. 10112-10129.

Research output: Contribution to journalArticle

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
Thomas, Allen A ; Hunt, Kevin W. ; Newhouse, Brad ; Watts, Ryan J. ; Liu, Xingrong ; Vigers, Guy ; Smith, Darin ; Rhodes, Susan P. ; Brown, Karin D. ; Otten, Jennifer N. ; Burkard, Michael ; Cox, April A. ; Geck Do, Mary K. ; Dutcher, Darrin ; Rana, Sumeet ; Delisle, Robert K. ; Regal, Kelly ; Wright, Albion D. ; Groneberg, Robert ; Liao, Jiangpeng ; Scearce-Levie, Kimberly ; Siu, Michael ; Purkey, Hans E. ; Lyssikatos, Joseph P. / 8-tetrahydropyran-2-yl chromans : Highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 23. pp. 10112-10129.
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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).",
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AU - Liao, Jiangpeng

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