Journal: Scientific Reports

Article Title: QSAR Classification Models for Predicting the Activity of Inhibitors of Beta-Secretase (BACE1) Associated with Alzheimer’s Disease

doi: 10.1038/s41598-019-45522-3

Figure Lengend Snippet: Graphical representation of physicochemical and drug-like properties of the BACE1 dataset. ( A ) Dispersion of compounds regarding logP prediction (x-axis) and logBB prediction (y-axis). Colors are defined by % human oral absorption. ( B ) Dispersion of the dataset according to molecular weight (x-axis) and a parameter related to physical-chemical properties of commercially available drugs (y-axis). The color is defined by the number of violations of the rule of 5.

Article Snippet: But even with these critical points, this way, the inhibition of BACE1, is a promising therapeutic strategy for instance BACE1 inhibitors with a multitarget profile .

Techniques: Dispersion, Molecular Weight

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: Acta Neuropathologica Communications

Article Title: Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: rapid reversal by anti-Aß agents

doi: 10.1186/s40478-014-0175-x

Figure Lengend Snippet: A BACE1 inhibitor reverses the pre-plaque LTP deficit (a,b). Three-day treatment with the BACE1 inhibitor LY2886721 transiently restored the ability to induce LTP in 4.5 month-old TG rats. (a) In animals treated with LY2886721 (5 X 0.2 nmol injections i.c.v.), but not with vehicle, HFS triggered robust STP and LTP that was stable for at least 3 h. Left hand panel shows the time course of synaptic plasticity. Summary bar chart of STP and LTP in left hand panel. *P < 0.05 compared with vehicle. Insets show representative EPSP traces at the times indicated. Calibration bars: Vertical, 1.0 mV; horizontal, 10 ms. (b) The recovery from the impairment in synaptic plasticity lasted for less than a week in the LY2886721-treated group. The same HFS protocol applied either just before (pre) or one week after (post) the injections of LY2886721 (n = 6) failed to induce either STP or LTP. Data for individual animals are shown in the first two panels and summarized statistically in the bar charts. *P < 0.05 compared with pre. Values are the mean ± S.E.M. % pre-HFS baseline EPSP amplitude at 10 min (STP) or 3 h (LTP).

Article Snippet: The BACE1 (β–secretase 1) inhibitor LY2886721 (N-[3-[(4aS,7aS)-2-amino-4,4a,5,7-tetrahydrofuro[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide) (Axon Medchem, Groningen, The Netherlands) and γ-secretase inhibitor MRK-560 ( N -[ cis -4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide) (Tocris, Bristol, UK) were initially dissolved in dimethyl sulfoxide (DMSO, Sigma, Dorset, UK).

Techniques: