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Assay Detail

CHEMBL5730852

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Binding
In Vivo Inhibition of Beta-Secretase: Several animal models, including mouse, rat, dog, and monkey, may be used to screen for inhibition of beta-secretase activity in vivo following administration of a test compound sample. Animals used in this invention can be wild type, transgenic, or gene knockout animals. For example, the Tg2576 mouse model, prepared and conducted as described in Hsiao et al., 1996, Science 274, 99-102, and other non-transgenic or gene knockout animals are useful to analyze in vivo inhibition of Amyloid beta peptide (Abeta) production in the presence of inhibitory test compounds. Generally, 2 to 18 month old Tg2576 mice, gene knockout mice or non-transgenic animals are administered test compounds formulated in vehicles, such as cyclodextran, phosphate buffers, hydroxypropyl methylcellulose or other suitable vehicles. One to twenty-four hours following the administration of compound, animals are sacrificed, and brains as well as cerebrospinal fluid (CSF) and plasma are removed for analysis of A-beta levels and drug or test compound concentrations (Dovey et al., 2001, Journal of Neurochemistry, 76, 173-181) Beginning at time 0, animals are administered by oral gavage, or other means of delivery such as intravenous injection, an inhibitory test compound of up to 100 mg/kg in a standard, conventional formulation, such as 2% hydroxypropyl methylcellulose, 1% Tween80. A separate group of animals receive 2% hydroxypropyl methylcellulose, 1% Tween80 alone, containing no test compound, and serve as a vehicle-control group. At the end of the test period, animals are sacrificed and brain tissues, plasma or cerebrospinal fluid are collected. Brains are either homogenized in 10 volumes (w/v) of 0.2% diethylamine (DEA) in 50 mM NaCl (Best et al., 2005, Journal of Pharmacology and Experimental Therapeutics, 313, 902-908), or in 10 volumes of 0.5% TritonX-100 in Tris-buffered saline (pH at about 7.6). Homogenates are centrifuged at 355,000 g, 4° C. for 30 minutes. CSF or brain supernatants are then analyzed for the presence of A-beta peptide by specific sandwich ELISA assays based on ECL (Electrochemiluminescence) technology.
ChEMBL ↗
510
Total Activities
168
Compounds Tested
3
Activity Types
0
Assay Parameters

Assay Information

Assay Type Binding
Organism Homo sapiens
Confidence 9 — Direct single protein target
Curated By Autocuration

Target

Beta-secretase 1 (CHEMBL4822) ↗
Type SINGLE PROTEIN
Organism Homo sapiens

Publication

Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
(2017)

Activity Statistics

Type Count Avg pChEMBL Best pChEMBL
IC50 170 7.84 9.52
kon 170 - -
k_off 170 - -

Compounds Tested

Compound Name Phase Activities Best pChEMBL
CHEMBL6023127 — — 3 9.52
CHEMBL6045555 — — 3 9.48
CHEMBL5772436 — — 3 9.42
CHEMBL5847284 — — 3 9.40
CHEMBL6007390 — — 3 9.36
CHEMBL5973772 — — 3 9.32
CHEMBL5837889 — — 3 9.30
CHEMBL5746081 — — 3 9.27
CHEMBL5875827 — — 3 9.27
CHEMBL6050614 — — 3 9.26
CHEMBL5974242 — — 3 9.25
CHEMBL5877502 — — 3 9.25
CHEMBL5938817 — — 3 9.23
CHEMBL5862340 — — 3 9.23
CHEMBL5751398 — — 3 9.22
CHEMBL5829050 — — 3 9.22
CHEMBL5977725 — — 3 9.21
CHEMBL5809643 — — 3 9.15
CHEMBL5761187 — — 3 9.12
CHEMBL5960571 — — 3 9.12
CHEMBL5746511 — — 3 9.10
CHEMBL5762300 — — 3 9.08
CHEMBL3261078 — — 3 9.07
CHEMBL5909937 — — 3 9.06
CHEMBL5959201 — — 3 9.04
CHEMBL5967490 — — 3 9.04
CHEMBL5951673 — — 3 9.00
CHEMBL5979230 — — 3 9.00
CHEMBL5927021 — — 3 8.96
CHEMBL5934199 — — 3 8.94

Activity Data

Compound Name Type Rel. Value Units pChEMBL
CHEMBL6023127 — IC50 = 0.3 nM 9.52
CHEMBL6045555 — IC50 = 0.33 nM 9.48
CHEMBL5772436 — IC50 = 0.38 nM 9.42
CHEMBL5847284 — IC50 = 0.4 nM 9.40
CHEMBL6007390 — IC50 = 0.44 nM 9.36
CHEMBL5973772 — IC50 = 0.48 nM 9.32
CHEMBL5837889 — IC50 = 0.5 nM 9.30
CHEMBL5875827 — IC50 = 0.54 nM 9.27
CHEMBL5746081 — IC50 = 0.54 nM 9.27
CHEMBL6050614 — IC50 = 0.55 nM 9.26
CHEMBL5974242 — IC50 = 0.56 nM 9.25
CHEMBL5877502 — IC50 = 0.56 nM 9.25
CHEMBL5938817 — IC50 = 0.59 nM 9.23
CHEMBL5862340 — IC50 = 0.59 nM 9.23
CHEMBL5829050 — IC50 = 0.6 nM 9.22
CHEMBL5751398 — IC50 = 0.6 nM 9.22
CHEMBL5977725 — IC50 = 0.62 nM 9.21
CHEMBL5809643 — IC50 = 0.7 nM 9.15
CHEMBL5761187 — IC50 = 0.76 nM 9.12
CHEMBL5960571 — IC50 = 0.76 nM 9.12
CHEMBL5746511 — IC50 = 0.8 nM 9.10
CHEMBL5762300 — IC50 = 0.83 nM 9.08
CHEMBL3261078 — IC50 = 0.85 nM 9.07
CHEMBL5909937 — IC50 = 0.87 nM 9.06
CHEMBL5959201 — IC50 = 0.92 nM 9.04
CHEMBL5967490 — IC50 = 0.92 nM 9.04
CHEMBL5951673 — IC50 = 1.0 nM 9.00
CHEMBL5979230 — IC50 = 1.0 nM 9.00
CHEMBL5927021 — IC50 = 1.1 nM 8.96
CHEMBL5934199 — IC50 = 1.15 nM 8.94
CHEMBL6007960 — IC50 = 1.2 nM 8.92
CHEMBL5912175 — IC50 = 1.3 nM 8.89
CHEMBL5830553 — IC50 = 1.3 nM 8.89
CHEMBL5773698 — IC50 = 1.3 nM 8.89
CHEMBL5871917 — IC50 = 1.3 nM 8.89
CHEMBL5884268 — IC50 = 1.4 nM 8.85
CHEMBL5761952 — IC50 = 1.46 nM 8.84
CHEMBL5888477 — IC50 = 1.5 nM 8.82
CHEMBL5913324 — IC50 = 1.5 nM 8.82
CHEMBL5811873 — IC50 = 1.54 nM 8.81
CHEMBL5852162 — IC50 = 1.6 nM 8.80
CHEMBL5744660 — IC50 = 1.6 nM 8.80
CHEMBL5936711 — IC50 = 1.63 nM 8.79
CHEMBL5835872 — IC50 = 1.7 nM 8.77
CHEMBL5891177 — IC50 = 1.74 nM 8.76
CHEMBL5879182 — IC50 = 1.81 nM 8.74
CHEMBL3973607 — IC50 = 1.9 nM 8.72
CHEMBL5779259 — IC50 = 1.89 nM 8.72
CHEMBL5900107 — IC50 = 1.9 nM 8.72
CHEMBL5822539 — IC50 = 1.9 nM 8.72