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oxazine 89   Click here for help

GtoPdb Ligand ID: 6944

PDB Ligand
Compound class: Synthetic organic
Comment: The CF3-substituted 1,3, oxazine 89 was found by Roche to be an orally active BACE1 inhibitor with an excellent PD profile in mice and a long lasting Aβ40/42 reduction in the CSF of rats[1] 13 PDB structures have been submitted and one of the series may enter clinical development
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 7
Hydrogen bond donors 2
Rotatable bonds 5
Topological polar surface area 113.39
Molecular weight 421.12
XLogP 3.28
No. Lipinski's rules broken 0

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES N#Cc1ccc(nc1)C(=O)Nc1ccc(c(c1)C1(C)N=C(N)OC(C1)C(F)(F)F)F
Isomeric SMILES N#Cc1ccc(nc1)C(=O)Nc1ccc(c(c1)[C@@]1(C)N=C(N)O[C@@H](C1)C(F)(F)F)F
InChI InChI=1S/C19H15F4N5O2/c1-18(7-15(19(21,22)23)30-17(25)28-18)12-6-11(3-4-13(12)20)27-16(29)14-5-2-10(8-24)9-26-14/h2-6,9,15H,7H2,1H3,(H2,25,28)(H,27,29)/t15-,18-/m0/s1
InChI Key MELQHVBGGSKVJQ-YJBOKZPZSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
Bioactivity Comments
Enzymatic potency was strongly affected by fluorines introduced into the oxazine headgroup. A down configured CF3 group in 89 improved the binding affinity considerably (IC50 = 0.012 μM) compared to unsubstituted 1b (IC50 = 0.051 μM). This compound 89 showed dose-dependent inhibition of brain Aβ40 production in mice at 4 h oral post dose and time-dependent inhibition of CSF Aβ40/42 production in rats after an oral dose of 1 mg/kg.[1]
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
beta-secretase 1 Primary target of this compound Hs Inhibitor Competitive 7.9 pIC50 - 1
⤷ pIC50 7.9 (IC50 1.2x10-8 M) [1]