SEMAGACESTAT

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Synonyms
Status
Molecule Category UNKNOWN
UNII 3YN0602W4W
EPA CompTox DTXSID10235740

Structure

InChI Key PKXWXXPNHIWQHW-RCBQFDQVSA-N
Smiles CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N[C@@H]1C(=O)N(C)CCc2ccccc21
InChI
InChI=1S/C19H27N3O4/c1-11(2)16(23)18(25)20-12(3)17(24)21-15-14-8-6-5-7-13(14)9-10-22(4)19(15)26/h5-8,11-12,15-16,23H,9-10H2,1-4H3,(H,20,25)(H,21,24)/t12-,15-,16-/m0/s1

Physicochemical Descriptors

Property Name Value
Molecular Formula C19H27N3O4
Molecular Weight 361.44
AlogP 0.38
Hydrogen Bond Acceptor 4.0
Hydrogen Bond Donor 3.0
Number of Rotational Bond 5.0
Polar Surface Area 98.74
Molecular species NEUTRAL
Aromatic Rings 1.0
Heavy Atoms 26.0

Bioactivity

Mechanism of Action Action Reference
Gamma-secretase inhibitor INHIBITOR PubMed
Protein: Gamma-secretase
Description: Presenilin-1
Organism : Homo sapiens
P49768 ENSG00000080815
Protein: Gamma-secretase
Description: Presenilin-2
Organism : Homo sapiens
P49810 ENSG00000143801
Protein: Gamma-secretase
Description: Gamma-secretase subunit APH-1B
Organism : Homo sapiens
Q8WW43 ENSG00000138613
Protein: Gamma-secretase
Description: Nicastrin
Organism : Homo sapiens
Q92542 ENSG00000162736
Protein: Gamma-secretase
Description: Gamma-secretase subunit APH-1A
Organism : Homo sapiens
Q96BI3 ENSG00000117362
Protein: Gamma-secretase
Description: Gamma-secretase subunit PEN-2
Organism : Homo sapiens
Q9NZ42 ENSG00000205155
Targets EC50(nM) IC50(nM) Kd(nM) Ki(nM) Inhibition(%)
Enzyme Protease Aspartic protease Aspartic protease AD clan Aspartic protease A22A subfamily Aspartic protease A22A regulatory subfamily
126 3-200 - - -
Enzyme
126 3-200 - - -
Ion channel Other ion channel Miscellaneous ion channel Presenilin ER Ca2+ leak channel family
126 3-200 - - -
Assay Description Organism Bioactivity Reference
Inhibition of gamma-secretase expressed in CHO cells expressing wild type human recombinant APP assessed as amyloid beta40 aggregation None 28.0 nM
Inhibition of mouse notch expressed in CHO cells assessed as transactivation of soluble alkaline phosphatase reporter system Mus musculus 63.0 nM
Inhibition of gamma-secretase in human SHSY5Y cells expressing human recombinant APP assessed as decrease in total Abeta level after 24 hrs by DELFIA Homo sapiens 100.0 nM
Inhibition of gamma-secretase in human SHSY5Y cells expressing human recombinant APP assessed as amyloid beta40 formation by ELISA Homo sapiens 39.81 nM
Inhibition of gamma-secretase in human SHSY5Y cells expressing human recombinant APP assessed as amyloid beta42 formation by ELISA Homo sapiens 39.81 nM
Inhibition of gamma-secretase expressed in african green monkey CV1 cells coexpressing Gal4 DNA-binding/transactivation domain assessed as inhibition of notch processing by luciferase reporter assay None 316.23 nM
Inhibition of gamma-secretase in human SHSY5Y cells expressing human recombinant APP assessed as decrease in Abeta42 level after 24 hrs by DELFIA Homo sapiens 125.89 nM
Inhibition of gamma-secretase in human SHSY5Y cells expressing human recombinant APP assessed as increase in Abeta38 level after 24 hrs by DELFIA Homo sapiens 125.89 nM
Inhibition of gamma-secretase in human SHSY5Y cells expressing human recombinant APP assessed as effect on Abeta40 level after 24 hrs by DELFIA Homo sapiens 199.53 nM
Inhibition of gamma secretase-mediated amyloid beta (1 to 40) production None 15.0 nM
Inhibition of gamma secretase-mediated amyloid beta (1 to 40) production in human SH-SY5Y cells Homo sapiens 38.0 nM
Displacement of [3H]5-chloro-N-((2S,3R)-5,5,5-trifluoro-1-hydroxy-3-methylpentan-2-yl)thiophene-2-sulfonamide from gamma secretase in human SH-SY5Y cells by competitive binding assay Homo sapiens 38.0 nM
Inhibition of gamma secretase-mediated total amyloid beta production in healthy human plasma at 5 to 50 mg/kg Homo sapiens 40.0 %
Inhibition of gamma secretase-mediated total amyloid beta production in human plasma at 140 mg/kg measured at 6 hrs post-dose Homo sapiens 73.0 %
Inhibition of gamma secretase-mediated amyloid beta (1 to 40) production in plasma of patient with Alzheimer's disease at 40 mg/kg QD for 6 weeks Homo sapiens 38.0 %
Inhibition of gamma secretase-mediated total amyloid beta production in plasma of patient with Alzheimer's disease at 140 mg/kg/day, po for 14 weeks Homo sapiens 65.0 %
Inhibition of gamma secretase-mediated total amyloid beta production in human CSF at 140 mg/kg measured at 12 hrs post-dose Homo sapiens 52.0 %
Inhibition of partially purified human gamma-secretase-mediated cleavage of notch fusion protein measured after overnight incubation by ELISA Homo sapiens 3.2 nM
Inhibition of partially purified human gamma-secretase-mediated cleavage of MBP-APPc125Sw fusion protein measured after overnight incubation by ELISA Homo sapiens 7.9 nM
In vivo inhibition of gamma-secretase in human assessed as decrease in plasma amyloid beta (1 to 40) level at 5 to 50 mg, po once daily for 14 days measured up to 24 hrs post last dose by LC-MS/MS analysis relative to control Homo sapiens 38.2 %
In vivo inhibition of gamma-secretase in human assessed as decrease in CSF amyloid beta (1 to 40) level at 5 to 50 mg, po once daily for 14 days measured up to 24 hrs post last dose by LC-MS/MS analysis relative to control Homo sapiens 4.42 %
In vivo inhibition of gamma-secretase in human assessed as decrease in plasma amyloid beta (1 to 40) level at 100 mg, po once daily for 14 days measured up to 24 hrs post last dose by LC-MS/MS analysis relative to control Homo sapiens 58.2 %
In vivo inhibition of gamma-secretase in human assessed as decrease in plasma amyloid beta (1 to 40) level at 140 mg, po once daily for 14 days measured up to 24 hrs post last dose by LC-MS/MS analysis relative to control Homo sapiens 64.6 %
Inhibition of gamma secretase (unknown origin) Homo sapiens 10.9 nM
Inhibition of gamma secretase (unknown origin) mediated Notch signaling Homo sapiens 14.1 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 23.81 %
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 -0.07 % 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 -0.07 %

Cross References

Resources Reference
ChEBI 131158
ChEMBL CHEMBL520733
DrugBank DB12463
FDA SRS 3YN0602W4W
Guide to Pharmacology 6978
PDB ESF
PubChem 9843750
SureChEMBL SCHEMBL417581
ZINC ZINC000003989041
CONTENTS