In vitro and in vivo characterization of AS2643361, a novel and highly potent inosine 5′-monophosphate dehydrogenase inhibitor
In vitro and in vivo characterization of AS2643361, a novel and highly potent inosine 5′-monophosphate dehydrogenase inhibitor
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DOI：
10.1016/j.ejphar.2011.10.032
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发表时间：
2012-01-05
影响因子：
5
通讯作者：
Morokata, Tatsuaki
中科院分区：
文献类型：
--
作者：
Nakanishi, Tomonori;Kozuki, Yoshihiro;Morokata, Tatsuaki
肌苷 5'-单磷酸 (IMP) 脱氢酶是实体器官移植的关键靶点。为此，霉酚酸酯（MMF）的开发代表了移植医学的重大进步。在这里，我们研究了一种新型 IMP 脱氢酶抑制剂 AS2643361 在几种免疫学和非免疫学模型中的体外和体内药理作用。 AS2643361 对免疫细胞和内皮细胞增殖以及脂多糖刺激的 B 细胞产生抗体的体外抑制活性明显强于霉酚酸（MMF 的活性形式），尽管这些化合物对 IMP 脱氢酶的效力相似。在大鼠异位心脏移植模型中，以 10 或 20 mg/kg/天口服 AS2643361 单一疗法可将中位移植物存活时间分别从 6 天延长至 16 天和 19 天。在二硝基苯酚脂多糖刺激的大鼠中，口服 2.5、5 或 10 mg/kg/天的 AS2643361 可抑制抗体产生。体内针对同种异体抗原的抗体产生也受到 5 或 10 mg/kg/天 AS2643361 治疗的抑制。此外，AS2543361 治疗可有效抑制球囊损伤引起的内膜增厚，这是晚期同种异体移植物丢失的主要原因。总体而言，AS2643361 的体内活性比 MMF 强两倍以上。此外，胃肠道毒性被认为是 MMF 的剂量限制因素，AS2643361 治疗降低了胃肠道毒性。这些结果表明，AS2643361 比 MMF 具有更高的效力和更低的毒性，使其成为移植医学中治疗急性和慢性排斥反应的潜在候选者。 (C) 2011 Elsevier B.V. 保留所有权利。
Inosine 5'-monophosphate (IMP) dehydrogenase is a critical target in solid organ transplantation. To this end, the development of mycophenolate mofetil (MMF) represents a major advance in transplant medicine. Here, we investigated the in vitro and in vivo pharmacological effects of a novel IMP dehydrogenase inhibitor, AS2643361, in several immunological and non-immunological models. The in vitro inhibitory activity of AS2643361 on immune cell and endothelial cell proliferation and on antibody production from lipopolysaccharide-stimulated B cells, was significantly more potent than that of mycophenolic acid, the active form of MMF, despite the similar potency of these compounds on IMP dehydrogenase. In a rat heterotopic cardiac transplant model, monotherapy using orally administered AS2643361 at 10 or 20 mg/kg/day prolonged the median graft survival time from 6 to 16 and 19 days, respectively. In dinitrophenol-lipopolysaccharide stimulated rats, oral administration of AS2643361 at 2.5, 5 or 10 mg/kg/day resulted in suppression of antibody production. In vivo antibody production against alloantigen was also suppressed by AS2643361 treatment at 5 or 10 mg/kg/ day. Furthermore, treatment with AS2543361 effectively inhibited balloon injury induced-intimal thickening, which is a major cause of late allograft loss. Overall, the in vivo activity of AS2643361 was over two-fold more potent than that of MMF. In addition, gastrointestinal toxicity, considered a dose-limiting factor for MMF, was reduced with AS2643361 treatment. These results suggest AS2643361 has higher potency and less toxicity than MMF, making it a potential candidate for treatment of acute and chronic rejection in transplant medicine. (C) 2011 Elsevier B.V. All rights reserved.