LXE408 是一种口服有效的，非竞争性的，动素体选择性蛋白酶体 (proteasome) 抑制剂。LXE408 抑制 L. donovani 蛋白酶体 (IC50=0.04 μM) 和 L. donovani (EC50=0.04 μM)。LXE408 具有较弱的透过血脑屏障能力。LXE408 具有用于内脏利什曼病 (VL) 研究的潜力。
货号:ajcx37312
CAS:1799330-15-6
分子式:C23H18FN7O2
分子量：443.43
溶解度:N/A
纯度：98%
存储：Store at -20°C
库存：现货

Background:

LXE408 is an orally active, non-competitive and kinetoplastid-selective proteasome inhibitor. LXE408 has an IC50 of 0.04 μM for L. donovani proteasome and an EC50 of 0.04 μM for L. donovani. LXE408 has a low propensity to cross the blood brain barrier. LXE408 has the potential for visceral leishmaniasis (VL) research[1].

LXE408 (compound 1) can occupy the pocket as a ternary complex with the proteasome. LXE408 shows no inhibition of the hERG channel (IC50>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 T1/2 of 3.3 hours for mouse. LXE408 (3 mg/kg IV and 10 mg/kg PO) has a T1/2 of 3.8 hours, a CL of 2.1 mL/min•kg, and a Vss 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 T1/2 of 3.8 hours for male beagle dog. LXE408 (0.3 mg/kg IV and 10 mg/kg PO) has a T1/2 of 9.7 hours for male cynomolgus monkey[1].

[1]. Advait Nagle, et al. Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases. J Med Chem. 2020 Jul 15.