NADPH oxidase-IN-1 (compound 11) can cross cross the blood-brain barrier (BBB) with Pe value of 13.6 (10-6 cm/s), determined by parallel artificial membrane permeability assay (PAMPA assay)[1].
NADPH oxidase-IN-1 (1 nM-10 mM; 30 min) LPS-induced ROS generation in BV2 microglial cells in a dose-dependent manner[1].
NADPH oxidase-IN-1 (10 μM; 24 h) inhibits the mRNA expression of pro-inflammatory cytokines in BV2 cells[1].
NADPH oxidase-IN-1 (1 nM-10 mM; 24 h) also inhibits activation and migration of BV2 cells[1].
NADPH oxidase-IN-1 (compound 11) (30 mg/kg; p.o.; daily for 4 wk) attenuates MPTP induced microglia activation and diminishes dopaminergic neuronal damage in Parkinson's disease (PD) mice model[1].
NADPH oxidase-IN-1 is safe in both male and female mice following IV injection (10-300 mg/kg; single dose) and oral gavage (10-1000 mg/kg; single dose), respectively[1].
Pharmacokinetic profile in rats
| Parameters | C0 (μg/mL) | Cmax (μg/mL) | t1/2 (h) | Tmax (h) | AUClast (μg/h/mL) | ke (1/h) | Vd (L) | Vd/F (L) | Cl (L/h) | Cl/F (L/h) | F (%) |
| IV (2 mg/kg) | 1.70 | 0.79 | 0.468 | 1.32 | 0.211 | 0.217 | |||||
| PO (10 mg/kg) | 0.609 | 5.01 | [0.083-2] | 1.31 | 0.170 | 1.99 | 0.341 | 56.0 | |||
| PO (20 mg/kg) | 0.783 | 6.13 | [0.67-2] | 4.16 | 0.159 | 1.82 | 0.217 | 88.9 |
References:
[1]. Shim S, et al. Discovery of a NADPH oxidase inhibitor,(E)-3-cyclohexyl-5-(4-((2-hydroxyethyl)(methyl) amino) benzylidene)-1-methyl-2-thioxoimidazolidin-4-oneone, as a novel therapeutic for Parkinson's disease[J]. European Journal of Medicinal Chemistry, 2022, 244: 114854.