oxazine 89   

GtoPdb Ligand ID: 6944

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
2D Structure
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Physico-chemical Properties
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
SMILES / InChI / InChIKey
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
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
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
beta-secretase 1 Hs Inhibitor Competitive 7.9 pIC50 - 1
pIC50 7.9 (IC50 1.2x10-8 M) [1]