Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany.
J Med Chem. 2020 Jul 9;63(13):7081-7107. doi: 10.1021/acs.jmedchem.0c00407. Epub 2020 Jun 17.
Phosphine oxides and related phosphorus-containing functional groups such as phosphonates and phosphinates are established structural motifs that are still underrepresented in today's drug discovery projects, and only few examples can be found among approved drugs. In this account, the physicochemical and properties of phosphine oxides and related phosphorus-containing functional groups are reported and compared to more commonly used structural motifs in drug discovery. Furthermore, the impact on the physicochemical properties of a real drug scaffold is exemplified by a series of phosphorus-containing analogs of imatinib. We demonstrate that phosphine oxides are highly polar functional groups leading to high solubility and metabolic stability but occasionally at the cost of reduced permeability. We conclude that phosphine oxides and related phosphorus-containing functional groups are valuable polar structural elements and that they deserve to be considered as a routine part of every medicinal chemist's toolbox.
氧化膦和相关的含磷官能团，如膦酸酯和膦酸盐，是已经确立的结构基序，但在当今的药物发现项目中仍然代表性不足，在已批准的药物中也只有少数例子。在本报告中，我们报告了氧化膦和相关含磷官能团的物理化学性质，并将其与药物发现中更常用的结构基序进行了比较。此外，通过一系列伊马替尼的含磷类似物，我们举例说明了对实际药物支架物理化学性质的影响。我们证明氧化膦是高度极性的官能团，导致高溶解度和代谢稳定性，但偶尔会以降低渗透性为代价。我们得出结论，氧化膦和相关的含磷官能团是有价值的极性结构单元，它们应该被视为每个药物化学家工具包的常规组成部分。
