DN-1289 is an orally active and selective inhibitor of dual leucine zipper kinase (DLK; IC50=17 nM) and leucine zipper-bearing kinase (LZK; IC50=40 nM). DN-1289 results significant attenuation of optic nerve crush (ONC)-induced p-c-Jun in mice model. DN-1289 has excellent in vivo plasma half-life and blood-brain barrier permeability.
DN-1289 (compound 14) (0.1, 0.3, and 1 μM; 0-20 h) can block axon degeneration in dorsal root ganglion (DRG) neurons induced by nerve growth factor (NGF) withdrawal[1].
DN-1289 (0.1, 0.3, and 1 μM; 0-20 h) inhibits the activation of caspases in DRG neurons over time induced by NGF withdrawal[1].
DN-1289 (compound 14) (100 mg/kg and 150 mg/kg; i.p.; once daily for 10-15 d) is well-tolerated in mice model[1].
DN-1289 (150 mg/kg; p.o.; b.i.d. for 10 d) inhibits phosphorylation of c-Jun in an acute injury model with optic nerve crush (ONC) application[1].
Pharmacokinetic Analysis[1]
| Species | Route | Dose (mg/kg) | plasma Cmax (μM) | plasma AUC0-24 h (μM·h) | CLp (mL/min/kg) | CLu (mL/min/kg) | Vd (L/kg) | t1/2 (h) | F (%) | Kpuu (AUC) | brain AUC0-2 h (μM·h) |
| rat | IV | 1 | 1.09 | 2.42 | 14.7 | 150 | 6.7 | 6.5 | / | 0.6 | 4.05 |
| PO | 3 | 0.58 | 3.9 | / | / | / | 4.6 | 52 | / | / | |
| mouse | IV | 1 | 1.06 | 4.06 | 8.6 | 200 | 4.7 | 6.8 | / | / | / |
| PO | 10 | 2.32 | 21.9 | / | / | / | 7.9 | 56 | 0.4 | 6.91 | |
| PO | 150 | 24.9 | 324 | / | / | / | 23.7 | 53 | / | / | |
| IP | 100 | 15.4 | 280 | / | / | / | 23.7 | 53 | / | / | |
| cyno | IV | 0.5 | 0.746 | 2.79 | 6.1 | 64 | 3.4 | 7.9 | / | / | / |
GLPBIO has not independently confirmed the accuracy of these methods. They are for reference only.
References:
[1]. Craig RA 2nd, et al. Discovery of Potent and Selective Dual Leucine Zipper Kinase/Leucine Zipper-Bearing Kinase Inhibitors with Neuroprotective Properties in In Vitro and In Vivo Models of Amyotrophic Lateral Sclerosis. J Med Chem. 2022 Dec 22;65(24):16290-16312.