| Identification | Back Directory | [Name]
KI-696 | [CAS]
1799974-70-1 | [Synonyms]
KI-696
KI-696,KI696
1H-Benzotriazole-5-propanoic acid, β-[3-[[(4R)-3,4-dihydro-4-methyl-1,1-dioxido-2H-5,1,2-benzoxathiazepin-2-yl]methyl]-4-methylphenyl]-7-methoxy-1-methyl-, (βS)- | [Molecular Formula]
C28H30N4O6S | [MDL Number]
MFCD31630709 | [MOL File]
1799974-70-1.mol | [Molecular Weight]
550.63 |
| Chemical Properties | Back Directory | [Boiling point ]
760.5±70.0 °C(Predicted) | [density ]
1.39±0.1 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
DMSO : 125 mg/mL (227.01 mM) | [form ]
Solid | [pka]
4.28±0.10(Predicted) | [color ]
White to off-white | [InChIKey]
ZDNGJXBUEQNFBQ-GCJKJVERSA-N | [SMILES]
[S]1(=O)(=O)N(C[C@H](Oc5c1cccc5)C)Cc2c(ccc(c2)[C@H](CC(=O)O)c3cc4nn[n](c4c(c3)OC)C)C |
| Hazard Information | Back Directory | [Uses]
KI696 is a high affinity probe that disrupts the Keap1/NRF2 interaction. KI696 is a potent and selective inhibitor of the KEAP1/NRF2 interaction[1]. | [Biological Activity]
KI-696 is a non-cytotoxic (10 mM; BEAS-2B cells)Kelch domain-targeing (Kd ~1.3 nM) KEAP1 selective inhibitor th at effectively upregulates nuclear NRF2 level in NHBE cells (%increase/[KI-696] = 100%/10 nM and 127%/100 nM; 6 hr) and NRF2 target genes transcription by blocking KEAP1-mediated NRF2 downregulation. KI-696 (5-50 mmol/kg i.v.) upregulates NRF2 target genes transcription in r at lungs in vivoas well as alleviate ozone-induced pulmonary inflammation and GSH depletion. KI-696 inhibits OATP1B1BSEPand PDE3A only at much higher concentrations (IC50 = 2.54.010 mMrespectively) and exhibits little or no potency toward a panel of 46 channelsenzymesand receptors. | [in vivo]
KI696 induces the expression of each of the Nqo1, Ho-1, Txnrd1, Srxn1, Gsta3, Gclc genes in a dose-dependent manner, with maximum increases over vehicle controls of 37-(Nqo1), 17-(Ho-1), 9-(Txnrd1), 28-(Srxn1), 15-(Gsta3) and 13-fold (Gclc) occurring at the 50 μmol/kg dose. EC50 values are 44.0, 25.7, 42.6, 33.8, 28.4, and 44.1 μmol/kg, respectively, giving an average EC50 value of 36.4±3.4 μmol/kg. KI696 attenuates ozone-Induced pulmonary inflammation. KI696 restores ozone-induced depletion of lung GSH levels. KI696 is administered to rats at 10, 35 and 50 μmol/kg by IV infusion, resulting in steady state compound concentrations in the blood of 407±44 nM, 946±50 nM and 1437±186 nM, respectively, over the 6 hour infusion period. Exposure to ozone 24 hours post-dose produces a significant depletion in lung levels of the anti-oxidant molecule, GSH, which is restored by KI696 in a dose-dependent manner[1]. | [References]
[1] Davies TG, et al. Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery. J Med Chem. 2016 Apr 28;59(8):3991-4006. DOI:10.1021/acs.jmedchem.6b00228 |
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