DP-155, a lecithin derivative of indomethacin, is a novel nonsteroidal antiinflammatory drug for analgesia and alzheimer's disease therapy
DP-155, a lecithin derivative of indomethacin, is a novel nonsteroidal antiinflammatory drug for analgesia and alzheimer's disease therapy
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DOI：
10.1111/j.1527-3458.2007.00014.x
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发表时间：
2007-06-01
期刊：
影响因子：
--
通讯作者：
Friedman, Jonathan E.
中科院分区：
文献类型：
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作者：
Dvir, Eran;Elman, Anat;Friedman, Jonathan E.
DP-155是吲哚美辛的脂质前药，由后者通过一个5碳长度的连接剂在sn-2位置偶联到卵磷脂。它被磷脂酶A(2) (PLA)(2)切割的程度比具有2、3和4个碳连接的类似化合物更大。吲哚美辛是DP-155在大鼠血清中的主要代谢物，口服DP-155后，代谢物在血清和脑中的半衰期分别为22和93 h，而口服吲哚美辛后的半衰期分别为10和24 h。DP-155的脑血清比吲哚美辛高3.5倍。体外研究表明DP-155是一种选择性环氧合酶(COX)-2抑制剂。裂解后，其吲哚美辛衍生物非选择性地抑制COX-1和-2。DP-155表现出较好的毒性特征，可能是由于其吲哚美辛代谢物的持续低血清水平和最大浓度降低。DP-155在测试的最高急性剂量（0.28 mmol/kg）下不产生胃毒性，而吲哚美辛在低33倍剂量下引起胃溃疡。此外，与吲哚美辛相比，反复口服给药后，DP-155的胃肠道和肾脏毒性更低（分别为10倍和5倍），并且延迟。除了降低毒性外，DP-155在解热和镇痛模型中具有与吲哚美辛相似的改善作用。此外，DP-155和吲哚美辛在降低转基因阿尔茨海默病小鼠（Tg2576）大脑中淀粉样蛋白β (A β)42水平以及在体外AD模型中减少A β 42细胞内摄取、神经变性和炎症方面同样有效。DP-155给药后脑内相对较高的吲哚美辛水平解释了尽管DP-155的全身血药浓度较低，但其疗效相同。与吲哚美辛相比，DP-155的安全性和同等疗效使其成为慢性治疗ad相关病理和镇痛的潜在候选药物。
DP-155 is a lipid prodrug of indomethacin that comprises the latter conjugated to lecithin at position sn-2 via a 5-carbon length linker. It is cleaved by phospholipase A(2) (PLA)(2) to a greater extent than similar compounds with linkers of 2, 3, and 4 carbons. Indomethacin is the principal metabolite of DP-155 in rat serum and, after DP-155 oral administration, the half-life of the metabolite was 22 and 93 h in serum and brain, respectively, compared to 10 and 24 h following indomethacin administration. The brain to serum ratio was 3.5 times higher for DP-155 than for indomethacin. In vitro studies demonstrated that DP-155 is a selective cyclooxygenase (COX)-2 inhibitor. After it is cleaved, its indomethacin derivative nonselectively inhibits both COX-1 and -2. DP-155 showed a better toxicity profile probably due to the sustained, low serum levels and reduced maximal concentration of its indomethacin metabolite. DP-155 did not produce gastric toxicity at the highest acute dose tested (0.28 mmol/kg), while indomethacin caused gastric ulcers at a dose 33-fold lower. Furthermore, after repeated oral dosing, gastrointestinal and renal toxicity was lower (10- and 5-fold, respectively) and delayed with DP-155 compared to indomethacin. In addition to reduced toxicity, DP-155 had similar ameliorative effects to indomethacin in antipyretic and analgesia models. Moreover, DP-155 and indomethacin were equally efficacious in reducing levels of amyloid beta (A beta)42 in transgenic Alzheimer's disease mouse (Tg2576) brains as well as reducing A beta 42 intracellular uptake, neurodegeneration, and inflammation in an in vitro AD model. The relatively high brain levels of indomethacin after DP-155 administration explain the equal efficacy of DP-155 despite its low systemic blood concentrations. Compared to indomethacin, the favored safety profile and equal efficacy of DP-155 establish the compound as a potential candidate for chronic use to treat AD-related pathology and for analgesia.