P-Glycoprotein (Pgp)-mediated cellular efflux is recognized as a common challenge in CNS drug discovery. In this study, the influence of replacing a hydrogen atom with fluorine on the pK_a and Pgp-mediated efflux is elucidated for a series of PDE9 inhibitors. The PDE9 inhibitors with and without fluorine were synthesized using a novel condensation–oxidation approach, providing access to several analogues, all from the same stereoenriched aldehyde building block. The incorporation of fluorine was found to influence two acid–base functionalities concomitantly, both of which were involved in Pgp-recognition. By methylating the acidic functionality, it was possible to isolate the effect responsible for lowering the Pgp-mediated efflux.

中文翻译：

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阐明氟对一系列PDE9抑制剂对p K _a的影响以及体外Pgp介导的流出†

P-糖蛋白（Pgp）介导的细胞外排被认为是中枢神经系统药物发现中的常见挑战。在这项研究中，对于一系列PDE9抑制剂，阐明了用氟取代氢原子对p K _a和Pgp介导的外排的影响。使用新颖的缩合-氧化方法合成了含氟和不含氟的PDE9抑制剂，可从同一个立体富集的醛结构单元中获得多种类似物。发现氟的结合会同时影响两个酸碱官能度，这两个都与Pgp识别有关。通过甲基化酸性官能团，可以分离出降低Pgp介导的外排的作用。