LXE408 is an orally active, kinetoplastid-selective proteasome inhibitor, exhibiting non-competitive inhibitory effects. It demonstrates an IC50 of 0.04 μM for L. donovani proteasome and an EC50 of 0.04 μM for L. donovani. Moreover, LXE408 shows limited ability to traverse the blood-brain barrier. Hence, LXE408 holds promise for advancing research in the field of visceral leishmaniasis (VL).

LXE408 (compound 1) can occupy the pocket as a ternary complex with the proteasome. LXE408 shows no inhibition of the hERG channel (IC 50 >30 μM) in a manual patch clamp assay. LXE408 has a low propensity to cross the blood brain barrier (brain/plasma AUC ratio=0.03 in mice)[1].

LXE408 (compound 1; 0.3-10 mg/kg; PO; twice daily for 8 days) potently reduces the parasite burden in the liver in a dose-dependent manner[1]. LXE408 (1, 3, 10, 20 mg/kg; p.o.; b.i.d.; for 10 days) effects robust healing of parasite-induced skin lesions at the base of the tail in BALB/c mice infected with L. major[1]. LXE408 (5 mg/kg IV and 20 mg/kg PO) has a T 1/2 of 3.3 hours for mouse. LXE408 (3 mg/kg IV and 10 mg/kg PO) has a T 1/2 of 3.8 hours, a CL of 2.1 mL/min?kg, and a V ss of 0.53 L/kg for male Sprague-Dawley rat[1]. LXE408 (0.3 mg/kg IV and 1.0 mg/kg PO) has a T 1/2 of 3.8 hours for male beagle dog. LXE408 (0.3 mg/kg IV and 10 mg/kg PO) has a T 1/2 of 9.7 hours for male cynomolgus monkey[1]. Animal Model: Female BALB/c mice (6-8 weeks old) infected with L. donovani[1]Dosage: 0.3, 1, 3, 10 mg/kg Administration: PO; twice daily for 8 days Result: Led to a 95% and >99.84% reduction of parasite burden in the liver at 1 mg/kg and 10 mg/kg. Animal Model: Balb/C mice[1]Dosage: 5 mg/kg IV and 20 mg/kg PO (Pharmacokinetic Analysis) Administration: IV or PO Result: Had a T 1/2 of 3.3 hours, a CL of 2.3 mL/min?kg, and a V ss of 0.63 L/kg for mouse.