Matsumoto Naoki, Suzuki Eriko, Tsujihara Kota, Nishimura Yuuichi, Hasumi Keiji
Department of Applied Biological Science, Tokyo Noko University, Tokyo, Japan.
Division of Research and Development, TMS Co., Ltd, Tokyo, Japan.
J Antibiot (Tokyo). 2015 Nov;68(11):685-90. doi: 10.1038/ja.2015.58. Epub 2015 May 13.
A family of fungal metabolites, SMTP, is a small-molecule plasminogen modulator that enhances plasminogen activation, leading to thrombolysis. We recently demonstrated that SMTP-7 effectively treats ischemic stroke due to its thrombolytic activity as well as anti-inflammatory action, which is attributable to soluble epoxide hydrolase (sEH) inhibition. In this paper, we studied detailed structure-activity relationships of plasminogen modulation and sEH inhibition using 25 SMTP congeners including six newly synthesized ones. The results clearly demonstrate that the structure of the N-linked side chain of SMTP congeners markedly affect their activities toward plasminogen modulation and inhibitions of the two activities of sEH (C-terminal epoxide hydrolase and N-terminal phosphatase). A slight change in the N-linked side chain results in affording selectivity of SMTP congeners. Many congeners, which lacked plasminogen modulation activity, differently inhibited the two sEH activities depending on the structures of the N-linked side chain. Some congeners were active in plasminogen modulation and inhibition of both activities of sEH. These results help comprehensive understanding of ideal design of a drug useful for ischemic diseases that are associated with inflammation, such as stroke.
一类真菌代谢产物SMTP是一种小分子纤溶酶原调节剂，可增强纤溶酶原激活，从而导致溶栓作用。我们最近证明，SMTP-7因其溶栓活性以及抗炎作用（这归因于可溶性环氧化物水解酶（sEH）抑制）而能有效治疗缺血性中风。在本文中，我们使用包括6个新合成的在内的25种SMTP同系物研究了纤溶酶原调节和sEH抑制的详细构效关系。结果清楚地表明，SMTP同系物N-连接侧链的结构显著影响它们对纤溶酶原调节的活性以及对sEH的两种活性（C端环氧化物水解酶和N端磷酸酶）的抑制作用。N-连接侧链的轻微变化导致SMTP同系物具有选择性。许多缺乏纤溶酶原调节活性的同系物，根据N-连接侧链的结构不同地抑制sEH的两种活性。一些同系物在纤溶酶原调节和抑制sEH的两种活性方面都有活性。这些结果有助于全面理解用于治疗与炎症相关的缺血性疾病（如中风）的理想药物设计。
