Target nature :
human DHODH
CAS n° :
1800296-63-2
Mecanism of action :
inhibition of the human DHODH catalytic activity
Physico-chemical properties :
- Molecular weight: 403.41 g/mol
- Experimental solubility: PBS pH7.4 with 10% cremophor EL: 4.2 ± 0.2 mM; PBS pH7.4 with 10% solutol HS15: 3.6 ± 0.1 mM
Probe availability :
upon request
Princeps reference :
Lucas-Hourani et al. (2015) J Med Chem. 58, 5579-5598 ; Munier-Lehmann, H et al.(2015) J Med Chem. 58, 860-877
More bibliography :
Grandin et al., 2016, Antiviral Research 125, 58-62.
Other available information on the probe :
- 3D structure of the human DHODH bound to IPPA17-A04: PDB6SYP.
- Metabolic stability on human and mice liver microsomes at 37°C: t1/2 = 42 and 7 min, respectively.
- Other analogues synthesized: 2-(3-Alkoxy-1H-pyrazol-1-yl)azines derivatives as well as 2-(3-Alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives
Other information on the target :
see review Munier-Lehmann et al., 2013, J. Med. Chem. 56(8), 314
Selectivity profile :
NA
In vivo data :
- IPPA17-A04 (administered topically with an intranasal sprayer) did not show any inhibitory effect against hRSV infection in macaques.
In vitro data :
- Inhibition of measles virus (IC50 = 0.021 µg/mL) and hRSV (IC50 = 5 nM) growth.
- Inhibitor of human DHODH enzymatic activity (tested on recombinant purified enzyme; IC50 = 25 nM)
Toxicity :
- Cell viability assay (CellTiterGlo reagent): CC50 > 500 µM (Hep2 and LLC-MK2 cells).
- Not toxic on cynomolgus macaques after 6 days of intravenous injections at 20 mg/kg/day (t1/2 in plasma = 10.1 ± 3.1 h for the last injection).
- CiToxLAB study report: IPPA17-A04 did not show any mutagenic activity in the bacterial reverse mutation test with Salmonella typhimurium, in the absence or the presence of a rat metabolizing system.
Chaine SMILES :
Cc2c(Oc1c(F)cccc1F)c(OC(C)C)nn2c4ncc(C3CC3)cc4F
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