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^[1]. 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)^[1] In Vitro: GNE-3511 has inhibitory activity for p-JNK and DRG with IC₅₀ values of 30 nM and 107 nM, respectively^[1].
GNE-3511 has kinase selectivity for MKK4, MKK7, JNK1, JNK2, JNK3, MLK1, MLK2 and MLK3 with IC₅₀ values of ＞5000 nM, ＞5000 nM, 129 nM, 514 nM, 364 nM, 67.8 nM, 767 nM and 602 nM, respectively^[1].
GNE-3511 displays concentration-dependent protection of neurons from degeneration in vitro^[1]. In Vivo: 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