Oxetanes as promising modules in drug discovery
Oxetanes as promising modules in drug discovery
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DOI：
10.1002/anie.200602343
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发表时间：
2006-01-01
影响因子：
16.6
通讯作者：
Carreira, Erick M.
中科院分区：
文献类型：
--
作者：
Wuitschik, Georg;Rogers-Evans, Mark;Carreira, Erick M.
在药物发现中，通常的做法是通过引入偕二甲基单元来阻断生物活性分子中的代谢暴露位点（图1）。然而，对于药物化学中的典型小分子，甲基取代氢原子导致其亲脂性显著增加，这反过来可能对其代谢和药代动力学特性产生不利影响。因此，一个稳定的，小的，亲脂性较低的分子模块，降低了对代谢攻击的敏感性将是一个非常理想的替代品。我们一直对易于方便合成和易于掺入生物活性化合物的模块感兴趣，并且认为氧杂环丁烷特别令人感兴趣。在这里，我们报告的离散氧杂环丁烷积木，这是很容易制备和连接到分子支架的合成。我们发现，纳入此基序的结果在显着改善的关键物理化学特性，并提供了宝贵的机会，性能指导的药物discovery.The计算的货车范德华体积的分析表明，氧杂环丁烷基单元和偕二甲基基团占据几乎相同的体积。这些计算与氧杂环丁烷和丙烷在水中的偏摩尔体积基本相同的实验结果一致。[1，2]我们选择将氧杂环丁烷结合到小分子上，以利用氧杂环丁烷的极性性质来降低亲脂性和代谢倾向。关于氧杂环丁烷的代谢和化学稳定性知之甚少，并且几乎没有与它们的掺入和随后在药理学感兴趣的化合物中的阐述相关的合成方法。紫杉醇，[3]氧杂环丁烷，[4]和氧杂环丁烷[5]-含氧杂环丁烷的生物活性物质的最佳研究--特别是包含2，3-二取代氧杂环丁烷;然而，氧杂环丁烷的内在化学和药理学性质（或内在优势）还远不清楚。
In drug discovery, it is common practice to block metabolically exposed sites in a biologically active molecule by the introduction of a gem-dimethyl unit (Figure 1). However, for a typical small molecule in medicinal chemistry, the replacement of hydrogen atoms by methyl groups leads to a significant increase in its lipophilicity, which in turn may adversely affect its metabolic and pharmacokinetic properties. Therefore, a stable, small, and less lipophilic molecular module with reduced susceptibility to metabolic attack would be a very desirable alternative. We have been interested in modules amenable to convenient synthesis and to facile incorporation into biologically active compounds, and have considered oxetanes to be of particular interest. Herein, we report the synthesis of discrete oxetane building blocks, which are readily prepared and attached onto molecular scaffolds. We show that incorporation of this motif results in remarkable improvements of key physicochemical characteristics and provides valuable opportunities for property-guided drug discovery.The analysis of the calculated van der Waals volumes reveals that an oxetanyl unit and a gem-dimethyl group occupy nearly the same volume. These calculations are in line with the experimental finding that the partial molar volumes of oxetane and propane in water are essentially the same.[1, 2] We chose to incorporate oxetanes onto small molecules to make use of the polar nature of the oxetane to reduce the lipophilicity and metabolic liability. Little is known about the metabolic and chemical stability of oxetanes, and there are few synthetic methodologies of relevance to their incorporation and subsequent elaboration in compounds of pharmacological interest. Taxol,[3] oxetanocin,[4] and oxetin [5]—the best studied of oxetane containing biological actives–--incorporate specifically 2, 3-disubstituted oxetanes; however, the intrinsic chemical and pharmacological properties (or inherent advantages) of the oxetanes are far from clear.