Fjelbye Kasper, Marigo Mauro, Clausen Rasmus P, Jørgensen Erling B, Christoffersen Claus T, Juhl Karsten
H. Lundbeck A/S , Ottiliavej 9 , 2500 Valby , Denmark . Email:
Department of Drug Design and Pharmacology , Faculty of Health and Medical Sciences , University of Copenhagen , 2 Universitetsparken , 2100 , Copenhagen , Denmark.
Medchemcomm. 2018 Apr 28;9(5):893-896. doi: 10.1039/c8md00114f. eCollection 2018 May 1.
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 p 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.
P-糖蛋白（Pgp）介导的细胞外排被认为是中枢神经系统药物研发中的一个常见挑战。在本研究中，针对一系列磷酸二酯酶9（PDE9）抑制剂，阐明了用氟取代氢原子对p和Pgp介导的外排的影响。采用新型缩合-氧化方法合成了含氟和不含氟的PDE9抑制剂，可从同一立体富集醛构建块获得多种类似物。研究发现，氟的引入会同时影响两个酸碱官能团，这两个官能团均参与Pgp识别。通过将酸性官能团甲基化，可以分离出导致Pgp介导的外排降低的效应。
