Biochem/physiol Actions

Reversible: yes

Primary TargetDLK

Cell permeable: yes

General description

A cell-permeable, orally bioavailable, blood-brain barrier permeant 2,6-diaminopyridine based compound that acts as a highly potent and selective inhibitor of dual leucine zipper kinase inhibitor (DLK; K_i = 500 pM). Exhibits an ideal balance of metabolic stability, potency, and efflux properties. Displays high selectivity over JNK (IC₅₀ = 129, 514, and 364 nM for JNK1, 2, and 3, respectively) and MLK (IC₅₀ = 67.8, 767, and 602 nM for MLK1, 2, and 3, respectively). Does not affect the activities of MKK4 and MKK7 (IC₅₀ >5 µM). Protects neurons in an in vitro axon degeneration assay (IC₅₀ = 107 nM). Also shown to reduce levels of phosphorylated c-Jun in retina and offer protection in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MTPT) model of Parkinson′s disease. Exhibits desirable pharmacokinetic properties (t1/2 = 0.6 h; CLp = 56 ml/min/kg in mice; 1 mg/kg, i.v., or 5 mg/kg; p.o.).Please note that the molecular weight for this compound is batch-specific due to variable water content. Please refer to the vial label or the certificate of analysis for the batch-specific molecular weight. The molecular weight provided represents the baseline molecular weight without water.

A cell-permeable, orally bioavailable, blood-brain barrier permeant 2,6-diaminopyridine based compound that acts as a highly potent and selective inhibitor of dual leucine zipper kinase inhibitor (DLK; K_i = 500 pM). Exhibits an ideal balance of metabolic stability, potency, and efflux properties. Displays high selectivity over JNK (IC₅₀ = 129, 514, and 364 nM for JNK1, 2, and 3, respectively) and MLK (IC₅₀ = 67.8, 767, and 602 nM for MLK1, 2, and 3, respectively). Does not affect the activities of MKK4 and MKK7 (IC₅₀ >5 µM). Protects neurons in an in vitro axon degeneration assay (IC₅₀ = 107 nM). Also shown to reduce levels of phosphorylated c-Jun in retina and offer protection in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MTPT) model of Parkinson′s disease. Exhibits desirable pharmacokinetic properties (t1/2 = 0.6 h; CLp = 56 ml/min/kg in mice; 1 mg/kg, i.v., or 5 mg/kg; p.o.).

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Other Notes

Patel, S., et al. 2014. J. Med. Chem. 57, in press.

Packaging

Packaged under inert gas

10 mg in Glass bottle

Reconstitution

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 3 months at -20°C.

Warning

Toxicity: Standard Handling (A)