Allylamine Derivatives—a New Class of Active Substances in Antifungal Chemotherapy
Allylamine Derivatives—a New Class of Active Substances in Antifungal Chemotherapy
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DOI：
10.1002/anie.198703201
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发表时间：
1987-04
影响因子：
--
通讯作者：
A. Stütz
中科院分区：
文献类型：
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作者：
A. Stütz
真菌感染（真菌病）在世界各地都有发现。目前只有少数结构类别的化合物在治疗中满足现代化疗的要求；因此，寻找新型活性物质具有重要的科学和治疗意义。一类新物质的第一个代表——烯丙胺衍生物——即naftifine (（E)- n -甲基-n -（1-萘基甲基）-3-苯基烯丙胺）是偶然发现的，最近作为局部抗真菌药在商业上可用。在纳替芬的基础上对结构-活性关系的探索和新的合成策略导致了该类型中目前最活跃的化合物特比萘芬的发现，特比萘芬是第一个含有(E)- 1,3 -炔结构元素的药物。特比萘芬在体内和体外都比原来的“铅”结构的纳替芬具有更高的活性；在局部或口服给药后，在各种化疗动物试验中，它也比标准制剂有效一个数量级。根据迄今为止获得的临床经验，特比萘芬耐受性良好，对各种类型的真菌具有良好的活性。烯丙胺通过一种新机制作为真菌角鲨烯环氧化酶的有效选择性抑制剂，与其他类固醇生物合成抑制剂不同，它不依赖于细胞色素P450。
Fungal infections (mycoses) are found throughout the world. Only a few structural classes of compounds currently satisfy the demands of modern chemotherapy in their treatment; hence, the quest for new types of active substances is of major scientific and therapeutic importance. The first representative of a new class of substances–the allylamine derivatives–namely naftifine ((E)-N-methyl-N-(1-naphthylmethyl)-3-phenylallylamine) was discovered by accident and has recently become commercially available as a topical antimycotic. The exploration of structure-activity relationships on the basis of naftifine and new synthetic strategies led to the discovery of the currently most active compound of this type, terbinafine, the first pharmaceutical agent to contain a (E)-1, 3-enyne structural element. Terbinafine exhibits considerably higher activity than the original “lead” structure naftifine both in vitro and in vivo; it is also up to one order of magnitude more effective than standard preparations in various chemotherapeutic animal tests after topical or oral administration. According to clinical experience gained so far, terbinafine is well tolerated and shows promising activity against various types of mycoses. Allylamines act as potent, selective inhibitors of fungal squalene epoxidase via a novel mechanism, which, unlike in the case of other inhibitors of steroid biosynthesis, does not depend on cytochrome P450.