H2L5186303 is a selective lysophosphatidic acid receptor 2 (LPA₂; IC₅₀=9nM) antagonist[1-2]. H2L5186303 can inhibit cell proliferation and promote apoptosis by blocking the LPA₂ receptor, and H2L5186303 is used in research related to asthma and inflammatory diseases[3-4].
In vitro, HT1080-M6 cells, a highly invasive subline derived from HT1080 fibrosarcoma cells, were treated with H2L5186303 (0.1–10μM) for 0–72 hours. H2L5186303 dose-dependently and significantly inhibited LPA-induced cell motility and invasive activity[5]. HT22 hippocampal neuronal cells were treated with H2L5186303 (1nM to 1μM) in combination with LPA (1μM) or the tetracyclic antidepressants Mianserin (5μM) and Mirtazapine (15μM) for 24 hours. H2L5186303 showed no significant inhibitory effect on LPA-, Mianserin-, or Mirtazapine-induced ERK1/2 phosphorylation, H2L5186303 does not mediate signaling transduction via the LPA₂ receptor in hippocampal neurons[6].
In vivo, in a bronchopulmonary dysplasia (BPD) model, newborn C57BL/6 mice were intraperitoneally injected with H2L5186303 (1mg/kg) starting from postnatal day 1, every 2 days for 10 days. H2L5186303 significantly improved hyperoxia-induced pulmonary vascular malformation and alveolar simplification, and restored endothelial cell tube formation capacity by inhibiting the LPA2 downstream target EGR1[7]. In an ovalbumin (OVA)-induced allergic asthma model, BALB/c mice were intraperitoneally administered H2L5186303 (1mg/kg) 30 minutes before OVA sensitization or challenge. H2L5186303 significantly suppressed airway hyperresponsiveness, inflammatory cell infiltration (such as eosinophils and lymphocytes), mucus secretion, and the expression of Th2 cytokines (such as IL-4 and IL-13)[8].
References:
[1] Fells JI, Tsukahara R, Liu J, et al. Structure-based drug design identifies novel LPA3 antagonists. Bioorg Med Chem. 2009 Nov 1;17(21):7457-64.
[2] Liang Z, Yun CC. Compensatory Upregulation of LPA2 and Activation of the PI3K-Akt Pathway Prevent LPA5-Dependent Loss of Intestinal Epithelial Cells in Intestinal Organoids. Cells. 2022 Jul 20;11(14):2243.
[3] Ishimoto K, Minami K, Otagaki S, et al. Rapid establishment of highly migratory cells from cancer cells for investigating cellular functions. J Recept Signal Transduct Res. 2019 Jun;39(3):194-198.
[4] Deveci A, Hasna J, Bouron A. Inhibition of store-operated calcium channels by N-arachidonoyl glycine (NAGly): no evidence for the involvement of lipid-sensing G protein coupled receptors. Sci Rep. 2020 Feb 14;10(1):2649.
[5] Takahashi K, Minami K, Otagaki S, et al. Lysophosphatidic acid receptor-2 (LPA2) and LPA5 regulate cellular functions during tumor progression in fibrosarcoma HT1080 cells. Biochem Biophys Res Commun. 2018 Sep 18;503(4):2698-2703.
[6] Olianas MC, Dedoni S, Onali P. LPA1 is a key mediator of intracellular signalling and neuroprotection triggered by tetracyclic antidepressants in hippocampal neurons. J Neurochem. 2017 Oct;143(2):183-197.
[7] Chen X, Han D, Zeng Y, et al. Inhibition of lysophosphatidic acid receptor 2 attenuates neonatal chronic lung disease in mice by preserving vascular and alveolar development. Eur J Pharmacol. 2024 Dec 15;985:177120.
[8] Lee YJ, Im DS. Efficacy Comparison of LPA2 Antagonist H2L5186303 and Agonist GRI977143 on Ovalbumin-Induced Allergic Asthma in BALB/c Mice. Int J Mol Sci. 2022 Aug 28;23(17):9745.
H2L5186303是一种选择性的溶血磷脂酸2受体（LPA2；IC₅₀=9nM）的拮抗剂[1-2]。H2L5186303可通过抑制LPA2受体来抑制细胞增殖，促进细胞凋亡，H2L5186303可用于哮喘和炎症相关疾病的相关研究[3-4]。
在体外，H2L5186303（0.1-10μM）处理HT1080纤维肉瘤来源的高侵袭性HT1080-M6细胞0-72小时，H2L5186303以剂量依赖方式显著抑制LPA诱导的细胞运动和侵袭活性[5]。H2L5186303（1nM至1μM）分别和LPA（1μM）或四环类抗抑郁药米安色林（5μM）、米氮平（15μM）处理HT22海马神经元细胞24小时，H2L5186303对LPA、米安色林、米氮平诱导的ERK1/2磷酸化均无显著抑制作用，H2L5186303在海马神经元中不通过LPA2受体介导信号转导[6]。
在体内，在支气管肺发育不良（BPD）模型中，H2L5186303（1mg/kg）腹腔注射处理新生C57BL/6小鼠（从出生后第1天开始，每2天一次，持续10天），H2L5186303显著改善高氧诱导的肺血管畸形和肺泡简化，并通过抑制LPA2下游靶点EGR1恢复内皮细胞管形成能力[7]。在卵清蛋白（OVA）诱导的过敏性哮喘模型中，H2L5186303（1mg/kg）腹腔注射处理BALB/c小鼠（在OVA致敏或激发前30分钟给药），H2L5186303显著抑制气道高反应性、炎症细胞（如嗜酸性粒细胞和淋巴细胞）浸润、黏液分泌以及Th2细胞因子（如IL-4和IL-13）表达[8]。