Discovery of 7-tetrahydropyran-2-yl chromans

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors that reduce amyloid β-protein (Aβ) in the central nervous system

Allen A Thomas, Kevin W. Hunt, Matthew Volgraf, Ryan J. Watts, Xingrong Liu, Guy Vigers, Darin Smith, Douglas Sammond, Tony P. Tang, Susan P. Rhodes, Andrew T. Metcalf, Karin D. Brown, Jennifer N. Otten, Michael Burkard, April A. Cox, Mary K.Geck Do, Darrin Dutcher, Sumeet Rana, Robert K. Delisle, Kelly Regal & 7 others Albion D. Wright, Robert Groneberg, Kimberly Scearce-Levie, Michael Siu, Hans E. Purkey, Joseph P. Lyssikatos, Indrani W. Gunawardana

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

In an attempt to increase selectivity vs Cathepsin D (CatD) in our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyrano[4,3-b]chromene analogues was developed. Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Using structure-based design, substitutions to improve binding to both the S3 and S2′ sites of BACE1 were explored. An acyl guanidine moiety provided the most potent analogues. These compounds demonstrated 10-420 fold selectivity for BACE1 vs CatD, and were highly potent in a cell assay measuring Aβ1-40 production (5-99 nM). They also suffered from high efflux. Despite this undesirable property, two of the acyl guanidines achieved free brain concentrations (C free,brain) in a guinea pig PD model sufficient to cover their cell IC50s. Moreover, a significant reduction of Aβ1-40 in guinea pig, rat, and cyno CSF (58%, 53%, and 63%, respectively) was observed for compound 62.

Original languageEnglish (US)
Pages (from-to)878-902
Number of pages25
JournalJournal of Medicinal Chemistry
Volume57
Issue number3
DOIs
StatePublished - Jan 7 2014

Fingerprint

Guanidines
Chromans
Serum Amyloid A Protein
Cathepsin D
Amyloid beta-Protein Precursor
Guinea Pigs
Central Nervous System
Benzopyrans
Guanidine
Brain
Enzymes
Permeability

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery of 7-tetrahydropyran-2-yl chromans : β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors that reduce amyloid β-protein (Aβ) in the central nervous system. / Thomas, Allen A; Hunt, Kevin W.; Volgraf, Matthew; Watts, Ryan J.; Liu, Xingrong; Vigers, Guy; Smith, Darin; Sammond, Douglas; Tang, Tony P.; Rhodes, Susan P.; Metcalf, Andrew T.; Brown, Karin D.; Otten, Jennifer N.; Burkard, Michael; Cox, April A.; Do, Mary K.Geck; Dutcher, Darrin; Rana, Sumeet; Delisle, Robert K.; Regal, Kelly; Wright, Albion D.; Groneberg, Robert; Scearce-Levie, Kimberly; Siu, Michael; Purkey, Hans E.; Lyssikatos, Joseph P.; Gunawardana, Indrani W.

In: Journal of Medicinal Chemistry, Vol. 57, No. 3, 07.01.2014, p. 878-902.

Research output: Contribution to journalArticle

Thomas, AA, Hunt, KW, Volgraf, M, Watts, RJ, Liu, X, Vigers, G, Smith, D, Sammond, D, Tang, TP, Rhodes, SP, Metcalf, AT, Brown, KD, Otten, JN, Burkard, M, Cox, AA, Do, MKG, Dutcher, D, Rana, S, Delisle, RK, Regal, K, Wright, AD, Groneberg, R, Scearce-Levie, K, Siu, M, Purkey, HE, Lyssikatos, JP & Gunawardana, IW 2014, 'Discovery of 7-tetrahydropyran-2-yl chromans: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors that reduce amyloid β-protein (Aβ) in the central nervous system', Journal of Medicinal Chemistry, vol. 57, no. 3, pp. 878-902. https://doi.org/10.1021/jm401635n
Thomas, Allen A ; Hunt, Kevin W. ; Volgraf, Matthew ; Watts, Ryan J. ; Liu, Xingrong ; Vigers, Guy ; Smith, Darin ; Sammond, Douglas ; Tang, Tony P. ; Rhodes, Susan P. ; Metcalf, Andrew T. ; Brown, Karin D. ; Otten, Jennifer N. ; Burkard, Michael ; Cox, April A. ; Do, Mary K.Geck ; Dutcher, Darrin ; Rana, Sumeet ; Delisle, Robert K. ; Regal, Kelly ; Wright, Albion D. ; Groneberg, Robert ; Scearce-Levie, Kimberly ; Siu, Michael ; Purkey, Hans E. ; Lyssikatos, Joseph P. ; Gunawardana, Indrani W. / Discovery of 7-tetrahydropyran-2-yl chromans : β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors that reduce amyloid β-protein (Aβ) in the central nervous system. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 3. pp. 878-902.
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AU - Watts, Ryan J.

AU - Liu, Xingrong

AU - Vigers, Guy

AU - Smith, Darin

AU - Sammond, Douglas

AU - Tang, Tony P.

AU - Rhodes, Susan P.

AU - Metcalf, Andrew T.

AU - Brown, Karin D.

AU - Otten, Jennifer N.

AU - Burkard, Michael

AU - Cox, April A.

AU - Do, Mary K.Geck

AU - Dutcher, Darrin

AU - Rana, Sumeet

AU - Delisle, Robert K.

AU - Regal, Kelly

AU - Wright, Albion D.

AU - Groneberg, Robert

AU - Scearce-Levie, Kimberly

AU - Siu, Michael

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AU - Lyssikatos, Joseph P.

AU - Gunawardana, Indrani W.

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N2 - In an attempt to increase selectivity vs Cathepsin D (CatD) in our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyrano[4,3-b]chromene analogues was developed. Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Using structure-based design, substitutions to improve binding to both the S3 and S2′ sites of BACE1 were explored. An acyl guanidine moiety provided the most potent analogues. These compounds demonstrated 10-420 fold selectivity for BACE1 vs CatD, and were highly potent in a cell assay measuring Aβ1-40 production (5-99 nM). They also suffered from high efflux. Despite this undesirable property, two of the acyl guanidines achieved free brain concentrations (C free,brain) in a guinea pig PD model sufficient to cover their cell IC50s. Moreover, a significant reduction of Aβ1-40 in guinea pig, rat, and cyno CSF (58%, 53%, and 63%, respectively) was observed for compound 62.

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