LANABECESTAT

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Search structure


Synonyms	AZD-3293 AZD3293 LY-3314814 LY3314814 Lanabecestat
Status
Molecule Category	UNKNOWN
UNII	X8SPJ492VF


Active Pharmaceutical Ingredients Bioactive chemicals	Exact Similarity SubStructure	Threshold (%) >= 70

Structure


InChI Key	WKDNQONLGXOZRG-HRNNMHKYSA-N
Smiles	CC#Cc1cncc(-c2ccc3c(c2)[C@@]2(N=C(C)C(N)=N2)[C@]2(CC[C@H](OC)CC2)C3)c1
InChI	InChI=1S/C26H28N4O/c1-4-5-18-12-21(16-28-15-18)19-6-7-20-14-25(10-8-22(31-3)9-11-25)26(23(20)13-19)29-17(2)24(27)30-26/h6-7,12-13,15-16,22H,8-11,14H2,1-3H3,(H2,27,30)/t22-,25-,26-/m0/s1

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C26H28N4O
Molecular Weight	412.54
AlogP	4.24
Hydrogen Bond Acceptor	5.0
Hydrogen Bond Donor	1.0
Number of Rotational Bond	2.0
Polar Surface Area	72.86
Molecular species	NEUTRAL
Aromatic Rings	2.0
Heavy Atoms	31.0

Bioactivity

Mechanism of Action	Action	Reference
Beta-secretase 1 inhibitor	INHIBITOR	PubMed


Protein: Beta-secretase 1 Description: Beta-secretase 1 Organism : Homo sapiens P56817 ENSG00000186318

Targets	EC50(nM)	IC50(nM)	Kd(nM)	Ki(nM)	Inhibition(%)
Enzyme Protease Aspartic protease Aspartic protease AA clan Aspartic protease A1A subfamily	-	-	-	26	-

Assay Description	Organism	Bioactivity	Reference
TR-FRET Assay: The beta-secretase enzyme used in the TR-FRET is prepared as follows: The cDNA for the soluble part of the human beta-Secretase (AA 1-AA 460) was cloned using the ASP2-Fc10-1-IRES-GFP-neoK mammalian expression vector. The gene was fused to the Fc domain of IgG1 (affinity tag) and stably cloned into HEK 293 cells. Purified sBACE-Fc was stored in -80 C. in Tris buffer, pH 9.2 and had a purity of 40%.The enzyme (truncated form) was diluted to 6 ug/mL (stock 1.3 mg/mL) and the substrate (Europium)CEVNLDAEFK(Qsy7) to 200 nM (stock 120 uM) in reaction buffer (NaAcetate, chaps, triton x-100, EDTA pH4.5). The robotic systems Biomek FX and Velocity 11 were used for all liquid handling and the enzyme and substrate solutions were kept on ice until they were placed in the robotic system. Enzyme (9 ul) was added to the plate then 1 ul of compound in dimethylsulphoxide was added, mixed and pre-incubated for 10 minutes. Substrate (10 ul) was then added, mixed.	Homo sapiens	1.2 nM		TR-FRET Assay: The beta-secretase enzyme used in the TR-FRET is prepared as follows: The cDNA for the soluble part of the human beta-Secretase (AA 1-AA 460) was cloned using the ASP2-Fc10-1-IRES-GFP-neoK mammalian expression vector. The gene was fused to the Fc domain of IgG1 (affinity tag) and stably cloned into HEK 293 cells. Purified sBACE-Fc was stored in -80 C. in Tris buffer, pH 9.2 and had a purity of 40%.The enzyme (truncated form) was diluted to 6 ug/mL (stock 1.3 mg/mL) and the substrate (Europium)CEVNLDAEFK(Qsy7) to 200 nM (stock 120 uM) in reaction buffer (NaAcetate, chaps, triton x-100, EDTA pH4.5). The robotic systems Biomek FX and Velocity 11 were used for all liquid handling and the enzyme and substrate solutions were kept on ice until they were placed in the robotic system. Enzyme (9 ul) was added to the plate then 1 ul of compound in dimethylsulphoxide was added, mixed and pre-incubated for 10 minutes. Substrate (10 ul) was then added, mixed.	Homo sapiens	25.0 nM
Inhibition of recombinant human BACE1 (1 to 460 residues) using CEVNLDAEFK as substrate preincubated for 10 mins followed by substrate addition measured after 6.5 hrs by TR-FRET assay	Homo sapiens	26.0 nM
Inhibition of human BACE2 (1 to 473 residues) using CEVNLDAEFK as substrate preincubated for 10 mins followed by substrate addition measured after 6.5 hrs by TR-FRET assay	Homo sapiens	372.0 nM
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate	Severe acute respiratory syndrome coronavirus 2	11.43 %
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging	Chlorocebus sabaeus	-0.18 %		Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging	Chlorocebus sabaeus	-0.18 %

Cross References

Resources	Reference
ChEMBL	CHEMBL3989948
DrugBank	DB14814
FDA SRS	X8SPJ492VF
Guide to Pharmacology	7789
PubChem	67979346
SureChEMBL	SCHEMBL9947930

CONTENTS

PREMIER has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 875508. The JU receives support from the EU’s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). The views reflect only the authors’ perspective and the JU is not responsible for any use that may be made of the information this manuscript contains.

Elements of the website have been developed under projects PREMIER and the Biocenter Finland Drug Discovery and Chemical Biology network. CSC-IT is thanked for providing computational resources. Content of the website is provided without guarantee for correctness. Data has been collected and integrated from multiple public sources, for the largest: FDA, HUGO Gene Nomenclature Committee, ChEMBL, IUPHAR/BPS guide to pharmacology, Reactome, UniProt, and Ensembl. Credit is given to Ensembl for collecting species images (provided under public domain licences such as Wikimedia and NHGRI).