A novel, orally active LPA1 receptor antagonist inhibits lung fibrosis in the mouse bleomycin model
A novel, orally active LPA1 receptor antagonist inhibits lung fibrosis in the mouse bleomycin model
复制标题
DOI：
10.1111/j.1476-5381.2010.00828.x
复制
发表时间：
2010-08-01
影响因子：
7.3
通讯作者：
Lorrain, D. S.
中科院分区：
文献类型：
--
作者：
Swaney, J. S.;Chapman, C.;Lorrain, D. S.
背景和目的：本研究的目的是评估溶血磷脂酸受体LPA（1）选择性拮抗剂在治疗肺纤维化中的潜力。我们评价了高亲和力、选择性、口服LPA（1）拮抗剂（4 ′-{4-[（R）-1-（2-氯-苯基）-乙氧羰基氨基]-3-甲基-异恶唑-5-基}-联苯-4-基）-乙酸（AM 966）的体外和体内药理学性质。实验方法：使用重组和天然细胞培养物，通过钙通量和细胞趋化性测定，体外测定AM 966对LPA（1）受体的效力和选择性。在小鼠博莱霉素模型中，在几个时间点评估了AM 966减少组织损伤、血管渗漏、炎症和纤维化的体内功效。关键结果：AM 966是LPA（1）受体的有效拮抗剂，对该受体的选择性超过其他LPA受体。在体外，AM 966抑制稳定表达人LPA（1）受体的中国仓鼠卵巢细胞中LPA刺激的细胞内钙释放（IC 50 = 17 nM），并抑制表达LPA（1）受体的人IMR-90肺成纤维细胞中LPA诱导的趋化性（IC 50 = 181 nM）。小鼠经口给药后，AM 966表现出良好的药代动力学特征。在小鼠中，AM 966在肺内滴注博来霉素后的多个时间点减少肺损伤、血管渗漏、炎症和纤维化。AM 966还降低了乳酸脱氢酶活性和金属蛋白酶组织抑制剂-1，转化生长因子β 1，透明质酸和基质金属蛋白酶-7，在支气管肺泡灌洗液fluid.Conclusions和影响：这些研究结果表明，AM 966是一种有效的，选择性的，口服生物利用LPA（1）受体拮抗剂，可能是有益的治疗肺损伤和纤维化，以及其他疾病的特点是病理性炎症，水肿和纤维化。
Background and purpose:The aim of this study was to assess the potential of an antagonist selective for the lysophosphatidic acid receptor, LPA(1), in treating lung fibrosis We evaluated the in vitro and in vivo pharmacological properties of the high affinity, selective, oral LPA(1)-antagonist (4'-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid (AM966).Experimental approach:The potency and selectivity of AM966 for LPA(1) receptors was determined in vitro by calcium flux and cell chemotaxis assays using recombinant and native cell cultures. The in vivo efficacy of AM966 to reduce tissue injury, vascular leakage, inflammation and fibrosis was assessed at several time points in the mouse bleomycin model.Key results:AM966 was a potent antagonist of LPA(1) receptors, with selectivity for this receptor over the other LPA receptors. In vitro, AM966 inhibited LPA-stimulated intracellular calcium release (IC50 = 17 nM) from Chinese hamster ovary cells stably expressing human LPA(1) receptors and inhibited LPA-induced chemotaxis (IC50 = 181 nM) of human IMR-90 lung fibroblasts expressing LPA(1) receptors. AM966 demonstrated a good pharmacokinetic profile following oral dosing in mice. In the mouse, AM966 reduced lung injury, vascular leakage, inflammation and fibrosis at multiple time points following intratracheal bleomycin instillation. AM966 also decreased lactate dehydrogenase activity and tissue inhibitor of metalloproteinase-1, transforming growth factor beta 1, hyaluronan and matrix metalloproteinase-7, in bronchoalveolar lavage fluid.Conclusions and implications:These findings demonstrate that AM966 is a potent, selective, orally bioavailable LPA(1) receptor antagonist that may be beneficial in treating lung injury and fibrosis, as well as other diseases that are characterized by pathological inflammation, oedema and fibrosis.