GNE-3511

GNE-3511 is an orally active bioavailable and brain-penetrant dual leucine zipper kinase (DLK) inhibitor with a K i of 0.5 nM. GNE-3511 can cross the blood-brain-barrier and can be used for the research of neurodegenerative diseases In Vitro GNE-3511 has inhibitory activity for p-JNK and DRG with IC 50 values of 30 nM and 107 nM, respectively. GNE-3511 has kinase selectivity for MKK4, MKK7, JNK1, JNK2, JNK3, MLK1, MLK2 and MLK3 with IC 50 values of ＞5000 nM, ＞5000 nM, 129 nM, 514 nM, 364 nM, 67.8 nM, 767 nM and 602 nM, respectively. GNE-3511 displays concentration-dependent protection of neurons from degeneration in vitro. MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo GNE-3511 (oral gavage; 75 mg/kg; single) suppresses CYP-induced nociceptive behavior by inhibiting DLK in mice. GNE-3511 (oral gavage; 75 mg/kg; single) suppresses CYP-induced edema and hemorrhage in mouse bladder. 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. Pharmacokinetic Parameters of GNE-3511 (iv.; 1 mg/kg or po.; 5 mg/kg). species CL p (mL/min/kg Vd ss (L/kg t 1/2 (h) F (%) B u /P u CSF/P u 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 MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Cystitis mouse model 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. Animal Model: mouse, rat, cynomolgus and dogDosage: 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. IC50& Target:Ki: 0.5 nM (DLK),IC50: 30 nM (p-JNK), 107 nM (DRG),＞5000 nM (MKK4), ＞5000 nM (MKK7), 129 nM (JNK1),514 nM (JNK2), 364 nM (JNK3), 67.8 nM (MLK1), 767 nM (MLK2) and 602 nM (MLK3)

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