HAMI3379

HAMI3379 is the first reported potent and selective cysteinyl leukotrienes (CysLT₂) receptor antagonist and also identified as an antagonist of the orphan G protein-coupled receptor GPR17. HAMI3379 was initially developed to treat cardiovascular and inflammatory disorders^[1][2]. HAMI3379 also exerts neuroprotective effects by modulating microglial polarization and preserving blood–brain barrier integrity^[3].

In vitro, HAMI3379 (1μM) pretreatment on HEK293 cells stably expressing human CysLT₂ receptors for 1h significantly inhibited leukotriene C₄ (100nM; 6h) induced expression of Egr-1 and IL-8 at both mRNA and protein levels, as well as IL-8 release into the culture medium^[4]. HAMI3379 pretreatment (0, 0.001, 0.01, 0.1, 1μΜ) on murine microglial BV-2 cells for 30min before 24h incubation of LPS (100ng/ml) significantly inhibited LPS-induced phagocytosis and overproduction of the proinflammatory cytokines (TNF-α, IL-6, and IL-1β)^[5].

In vivo, HAMI3379 (0.1mg/kg) was administered intraperitoneally into post-stroke depression (PSD) gerbil model 30 minutes before and after transient global cerebral ischemia surgery, once daily for 14 days. HAMI3379 diminished PSD-induced neurological injury and depression-like behaviors in gerbils via suppressing the NLRP3 inflammasome/pyroptosis pathway^[6]. HAMI3379 (0.025, 0.05, 0.1, 0.2 and 0.4mg/kg) was administrated into Sprague–Dawley rats via intraperitoneal injection 30min before middle cerebral artery occlusion (MCAO). HAMI3379 (0.1–0.4mg/kg) significantly reduced the infarct volume and percentage increase in the ischemic/contralateral hemispheric ratio, significantly reduced the neurological deficit score and increased the holding angle in the inclined board test at 24h in a dose-dependent manner^[7].

References:
[1] Dong X W, Zhao Y M, Huang X Q, et al. Structure-based drug design using GPCR homology modeling: toward the discovery of novel selective CysLT2 antagonists. Eur J Med Chem. 2013 Apr:62:754-63.
[2] Merten N, Fischer J, Simon K, et al. Repurposing HAMI3379 to Block GPR17 and Promote Rodent and Human Oligodendrocyte Differentiation.Cell Chem Biol. 2018 Jun 21;25(6):775-786.e5.
[3] Chen K C, Lan K P, Lai S C. Neuroprotective effects of CysLT2R antagonist on Angiostrongylus cantonensis-induced edema and meningoencephalitis.Mol Biochem Parasitol. 2024 Dec:260:111649.
[4] Lin K, Fang S H, Cai B L, et al. ERK/Egr-1 signaling pathway is involved in CysLT2 receptor-mediated IL-8 production in HEK293 cells. Eur J Cell Biol. 2014 Jul;93(7):278-88.
[5] Chen L, Yang Y, Li C T, et al. CysLT2 receptor mediates lipopolysaccharide-induced microglial inflammation and consequent neurotoxicity in vitro. Brain Res. 2015 Oct 22:1624:433-445.
[6] Zhou L, Zhang J J, Han X, et al. CysLT2R Antagonist HAMI3379 Ameliorates Post-Stroke Depression through NLRP3 Inflammasome/Pyroptosis Pathway in Gerbils. Brain Sci. 2022 Jul 24;12(8):976.
[7] Shi Q J, Wang H, Liu Z X, et al. HAMI3379, a CysLT2R antagonist, dose- and time-dependently attenuates brain injury and inhibits microglial inflammation after focal cerebral ischemia in rats. Neuroscience. 2015 Apr 16:291:53-69.

HAMI3379是首个被报道的强效选择性半胱氨酰白氧合肽（CysLT₂）受体拮抗剂，也被鉴定为孤儿G蛋白偶联受体GPR17的拮抗剂。HAMI3379最初开发用于心血管及炎症性疾病^[1][2]。HAMI3379也通过调控小胶质细胞极化并维持血脑屏障完整性发挥神经保护作用^[3]。

体外实验中，1μM HAMI3379预处理稳定表达人CysLT₂受体的HEK293细胞1h，可显著抑制白三烯C4（100nM；6h）诱导的Egr-1与IL-8在mRNA及蛋白水平的表达，并减少IL-8在培养基中的释放^[4]。HAMI3379（0、0.001、0.01、0.1、1μM）预处理小鼠小胶质BV-2细胞30min后再给予LPS（100ng/ml）刺激24h，显著抑制LPS诱导的吞噬作用及促炎细胞因子（TNF-α、IL-6和IL-1β）的过度产生^[5]。

体内实验中，HAMI3379（0.1mg/kg）在短暂性全脑缺血手术前后30min即刻腹腔注射于卒中后抑郁（PSD）沙鼠模型中，随后每日一次连续14天，可通过抑制NLRP3炎症小体/焦亡通路减轻沙鼠模型的神经损伤及抑郁样行为^[6]。HAMI3379（0.025、0.05、0.1、0.2和0.4mg/kg）在Sprague–Dawley大鼠模型大脑中动脉闭塞（MCAO）前30分钟通过腹腔注射给药，0.1–0.4mg/kg剂量范围内可显著减少梗死体积及缺血/对侧半球体积比，显著降低神经功能缺损评分，并在倾斜板试验中以剂量依赖方式提高维持角度^[7]。