Uncharged isocoumarin-based inhibitors of urokinase-type plasminogen activator.
Uncharged isocoumarin-based inhibitors of urokinase-type plasminogen activator.
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DOI：
10.1186/1472-6769-6-1
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发表时间：
2006-02-08
期刊：
影响因子：
--
通讯作者：
Vander Jagt DL
中科院分区：
文献类型：
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作者：
Heynekamp JJ;Hunsaker LA;Vander Jagt TA;Deck LM;Vander Jagt DL
尿激酶型纤溶酶原激活物（uPA）在与肿瘤细胞生长、迁移和血管生成相关的细胞外蛋白水解事件中起主要作用。因此，uPA是开发小分子活性位点抑制剂的有吸引力的靶标。针对uPA的非肽类抑制剂的大多数最近的药物开发计划都集中在含有连接到芳香族或杂环骨架的脒或胍官能团的氨基模拟物上。存在这些带电抑制剂的有限生物利用度的一般问题。在本研究中，uPA抑制剂的设计上的异香豆素支架含有不带电的取代基。合成了4-氯-3-烷氧基异香豆素，其中3-烷氧基含有末端溴;将其与含有带电末端官能团的类似抑制剂进行了比较。另外的变化包括连接到异香豆素支架的第七位的官能团。N- [3-（3-溴丙氧基）-4-氯-1-氧代-1H-异色烯-7-基]苯甲酰胺被鉴定为uPA的不带电荷的先导抑制剂，Ki = 0.034 μM。用这些不带电荷的抑制剂对人uPA的分子建模表明，溴占据与带正电荷的氨基模拟基团相同的位置。这项研究表明，有效的不带电荷的uPA抑制剂可以开发的基础上异香豆素支架。三位上的束缚溴和七位上的芳族基团是结合的重要贡献者。虽然目的是开发作为基于机制的灭活剂的化合物，但这些抑制剂是竞争性可逆抑制剂。
Urokinase-type plasminogen activator (uPA) plays a major role in extracellular proteolytic events associated with tumor cell growth, migration and angiogenesis. Consequently, uPA is an attractive target for the development of small molecule active site inhibitors. Most of the recent drug development programs aimed at nonpeptidic inhibitors targeted at uPA have focused on arginino mimetics containing amidine or guanidine functional groups attached to aromatic or heterocyclic scaffolds. There is a general problem of limited bioavailability of these charged inhibitors. In the present study, uPA inhibitors were designed on an isocoumarin scaffold containing uncharged substituents. 4-Chloro-3-alkoxyisocoumarins were synthesized in which the 3-alkoxy group contained a terminal bromine; these were compared with similar inhibitors that contained a charged terminal functional group. Additional variations included functional groups attached to the seven position of the isocoumarin scaffold. N- [3-(3-Bromopropoxy)-4-chloro-1-oxo-1H-isochromen-7-yl]benzamide was identified as an uncharged lead inhibitor of uPA, Ki = 0.034 μM. Molecular modeling of human uPA with these uncharged inhibitors suggests that the bromine occupies the same position as positively charged arginino mimetic groups. This study demonstrates that potent uncharged inhibitors of uPA can be developed based upon the isocoumarin scaffold. A tethered bromine in the three position and an aromatic group in the seven position are important contributors to binding. Although the aim was to develop compounds that act as mechanism-based inactivators, these inhibitors are competitive reversible inhibitors.