GNE-3511 is a selective and highly potent inhibitor of dual leucine zipper kinase (DLK). It also inhibits phosphorylated JNKand is highly selective for DLK over other MAP kinases. In an MPTP mouse model of Parkinson’s disease, a high dose of GNE-3511 completely suppresses phosphorylated c-Jun (p-c-Jun) expression, while a low dose moderately reduces its expression. Study has also shown that GNE03511 displayed concentration-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that GNE-3511 may have therapeutic potential in multiple indications.
Patel, S, et al. "Discovery of Dual Leucine Zipper Kinase (DLK, MAP3K12) Inhibitors with Activity in Neurodegeneration Models. " Journal of Medicinal Chemistry 58.1(2015):401-18.
https://www.caymanchem.com/product/19174
GNE-3511 is a potent and selective dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models. GNE-3511 displays concentration-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. GNE-3511 displays protection of primary neurons in an in vitro axon degeneration assay as well as activity in the mouse models of glaucoma/optic neuropathy (optic nerve crush) and Parkinson’s disease (MPTP) after oral dosing.
Cell permeable: yes', 'Primary Target
DLK', 'Reversible: yes
GNE-3511 (oral gavage; 75 mg/kg; single) suppresses CYP-induced nociceptive behavior by inhibiting DLK in mice[2].
GNE-3511 (oral gavage; 75 mg/kg; single) suppresses CYP-induced edema and hemorrhage in mouse bladder[2].
GNE-3511 (iv.; 1 mg/kg or po.; 5 mg/kg) exhibits moderate in vivo plasma clearances, moderate volumes of distribution, short half-lives, and brain penetration[2].
Pharmacokinetic Parameters of GNE-3511 (iv.; 1 mg/kg or po.; 5 mg/kg)[2].
| species | CLp (mL/min/kg | Vdss (L/kg | t1/2 (h) | F (%) | Bu/Pu | CSF/Pu |
| mouse | 56 | 2.5 | 0.6 | 45 | 0.24 at 6 h | |
| rat | 30 | 3.7 | 1.8 | 63 | 0.7 | 0.4 |
| dog | 41 | 6.5 | 4 | 32 | | 0.4 |
| cynomolgous | 16 | 3.1 | 2.4 | 19 | | 0.6 |
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| Animal Model: | Cystitis mouse model[1] |
| Dosage: | 75 mg/kg |
| Administration: | oral gavage;75 mg/kg; single |
| Result: | Significantly reduced the number of nociceptive behavior as well as nociceptive score.
Had no impact on bladder weight, did not induce bladder edema or hemorrhage and significantly suppressed CYP-induced increase in bladder weight, bladder edema, and hemorrhage.
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| Animal Model: | mouse, rat, cynomolgus and dog[2] |
| Dosage: | 1 mg/k, 5 mg/kg |
| Administration: | iv.; 1 mg/kg or po.; 5 mg/kg |
| Result: | Exhibited moderate in vivo plasma clearances, moderate volumes of distribution, short half-lives and brain penetration. |
