Journal: Drug Discovery Today. Technologies

Article Title: Expanding opportunities for mining bioactive chemistry from patents

doi: 10.1016/j.ddtec.2014.12.001

Figure Lengend Snippet: Examples of curated and annotated database mappings from patents. The upper panel shows part of the Guide to PHARMACOLOGY (GToPdb) entry ( http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6476 ) for AZD9668 as a clinically tested neutrophil elastase (UniProt P08246 ) inhibitor. The curator's notes and the two references are shown; including a SureChEMBL link to the patent US20070203129 (additional connectivity for this entry has been added for the next update). The lower panel shows one of the views on BindingDB for PubChem CID 44247663 from a US8541427 on BACE1 inhibitors.

Article Snippet: The first two documents, both published on May 1st 2014, were WO2014066132 from Eli Lilley [ ] and WO2014065434 from Shionogi [ ], both specifying BACE1 inhibitors for Alzheimer's disease (6132 used BACE as a synonym for BACE1, UniProt P56817 ).

Techniques:

Journal: Pharmaceuticals

Article Title: BACE-1 and γ-Secretase as Therapeutic Targets for Alzheimer’s Disease

doi: 10.3390/ph12010041

Figure Lengend Snippet: Chromane-based spirocyclic acyl guanidine-derived BACE-1 inhibitor 21 develop by Array BioPharma together with Genentech .

Article Snippet: Array BioPharma together with Genentech developed a series of chromane-based spirocyclic acyl guanidine-derived BACE-1 inhibitors leading to compound 21 ( ).

Techniques: Derivative Assay

Journal: Frontiers in Aging Neuroscience

Article Title: BACE1 Inhibitor MK-8931 Alters Formation but Not Stability of Dendritic Spines

doi: 10.3389/fnagi.2018.00229

Figure Lengend Snippet: BACE1 inhibitor MK-8931 altered plasticity of dendritic spines in vivo . (A) Micrographs of eGFP-labeled apical dendrites of layer V pyramidal neurons in somatosensory cortex before, during and after administration of vehicle or MK-8931. Treatment started 8 days after first imaging timepoint and was continued over 21 days, every 12 h. White arrowheads exemplarily mark representative spines which were stable over the entire imaging period. Newly gained spines are labeled with green arrowheads and lost spines are labeled with magenta arrowheads. (B) Quantification of spine density (C,D) fraction of gained and lost spines in mice treated with vehicle or MK-8931 (20 mg/kg). N = 5 animals per group, n = 10 dendrites per animal. Data is presented as mean ± SEM. Bonferroni post-hoc test results: * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001 from two-way ANOVA (day 0–28).

Article Snippet: The BACE1 inhibitor MK-8931 was synthesized following the schemes provided by FORUM Pharmaceuticals (Waltham, MA, USA) and formulated in 10% (w/v) 2-hydroxypropyl-beta-cyclodextrin.

Techniques: In Vivo, Labeling, Imaging

Journal: Frontiers in Aging Neuroscience

Article Title: BACE1 Inhibitor MK-8931 Alters Formation but Not Stability of Dendritic Spines

doi: 10.3389/fnagi.2018.00229

Figure Lengend Snippet: MK-8931 treatment did not cause spine elimination. (A) Spine stability and turnover rates in vehicle and MK-8931 treated mice. Daily turnover rate significantly decreased at the end of inhibitor treatment. (B,C) MK-8931 treatment significantly decreased density of transient spines, whereas density of stable spines was not affected. Bonferroni post-hoc test: ns: p = 0.4926, * p < 0.05, *** p < 0.001, **** p < 0.0001 (two-way ANOVA between day 0–28). (D) Survival rate of newly gained spines was not affected by BACE1 inhibitor treatment. N = 5 animals per group, n = 10 dendrites per animal. Two-tailed Student’s t -test, t (8) = 0.9, p = 0.394. Data presented as mean ± SEM.

Article Snippet: The BACE1 inhibitor MK-8931 was synthesized following the schemes provided by FORUM Pharmaceuticals (Waltham, MA, USA) and formulated in 10% (w/v) 2-hydroxypropyl-beta-cyclodextrin.

Techniques: Two Tailed Test

Journal: PLoS ONE

Article Title: Ferulic Acid Is a Nutraceutical β-Secretase Modulator That Improves Behavioral Impairment and Alzheimer-like Pathology in Transgenic Mice

doi: 10.1371/journal.pone.0055774

Figure Lengend Snippet: (A) Western blots are shown using an amino (N)-terminal APP polyclonal antibody (pAb N-APP; holo-APP is shown) and a carboxyl-terminal BACE1 polyclonal antibody (pAb BACE1). Western blots are also shown using an amino-terminal amyloid-β (Aβ) monoclonal antibody (mAb 82E1), which detects various amyloidogenic APP cleavage fragments including: Aβ monomer and oligomers as well as phospho-C99 (P-C99) and non-phospho-C99 (C99). Actin is shown as a loading control for each blot, and ratiometric densitometry data are shown below each lane. (B) Densitometry analyses are shown for ratios of C-99 or P-C99 to actin. (C) Aβ oligomers in the 2% SDS-soluble brain homogenate fraction were measured by sandwich ELISA. (D) Densitometry analysis is shown for ratio of BACE1 to actin. (E) α- and β-secretase activity assays are shown. Relative fluorescence units are depicted on the y-axis, and reaction time is represented on the x-axis. Representative Western blots for A were obtained from PSAPP mice treated with vehicle (PSAPP-V, n = 3) or with FA (PSAPP-FA, n = 3). Data for B-E were obtained from PSAPP mice treated with vehicle (PSAPP-V, n = 12) or with FA (PSAPP-FA, n = 12) for 6 months beginning at 6 months of age. All statistical comparisons are between PSAPP-V and PSAPP-FA mice.

Article Snippet: Briefly, BACE1 enzyme was incubated with various concentrations of FA (1.563, 3.125, 6.25, or 12.5 μM) or BACE1 inhibitor II (1.25 μM, as a positive control; Merck Millipore, Darmstadt, Germany) in the presence of 1×reaction buffer for 40 minutes prior to reading fluorescence values on a FLUOstar Omega (BMG LABTECH, San Diego, CA) fluorescent microplate reader.

Techniques: Western Blot, Control, Sandwich ELISA, Activity Assay, Fluorescence

Journal: PLoS ONE

Article Title: Ferulic Acid Is a Nutraceutical β-Secretase Modulator That Improves Behavioral Impairment and Alzheimer-like Pathology in Transgenic Mice

doi: 10.1371/journal.pone.0055774

Figure Lengend Snippet: (A) Amyloid-β (Aβ) 1–40 and Aβ 1–42 species were separately measured in cell supernatants from SweAPP N2a cells by sandwich ELISAs. (B) Inhibition of amyloidogenic APP processing in SweAPP N2a cells treated with various doses of FA. Western blots using an amino-terminal Aβ 1–17 monoclonal antibody (mAb 6E10), a carboxyl-terminal APP polyclonal antibody (pAb C-APP), or a carboxyl-terminal BACE1 polyclonal antibody (pAb BACE1) show holo-APP, carboxyl-terminal fragment generated by amyloidogenic APP cleavage (C99, β-CTF), and BACE1, respectively. Actin is included as an internal reference control, and ratiometric densitometry data are shown below each lane. (C) Densitometry results are shown as ratio of C99 to actin at various FA treatment doses. (D) Densitometry results are shown as ratio of BACE1 to actin at various FA treatment doses. (E) Quantitative real-time PCR results for BACE1 mRNA levels at various FA treatment doses are shown in arbitrary units, and BACE1 relative abundance is depicted on the y-axis. (F) Cell-free BACE1 activity assay results are displayed, and % of BACE1 activity is shown on the y-axis. (G) Lactate dehydrogenase (LDH) release assay results are shown for SweAPP N2a cells treated with 0 to 12.5 µM of FA. All statistical comparisons are vs. 0 µM of FA, and similar results were observed in 3–4 independent experiments.

Article Snippet: Briefly, BACE1 enzyme was incubated with various concentrations of FA (1.563, 3.125, 6.25, or 12.5 μM) or BACE1 inhibitor II (1.25 μM, as a positive control; Merck Millipore, Darmstadt, Germany) in the presence of 1×reaction buffer for 40 minutes prior to reading fluorescence values on a FLUOstar Omega (BMG LABTECH, San Diego, CA) fluorescent microplate reader.

Techniques: Inhibition, Western Blot, Generated, Control, Real-time Polymerase Chain Reaction, Activity Assay, Lactate Dehydrogenase Assay