Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK.
Bioorg Med Chem. 2019 Sep 15;27(18):3998-4012. doi: 10.1016/j.bmc.2019.06.027. Epub 2019 Jun 18.
Several 3',5'-cyclic nucleotide phosphodiesterases (PDEs) have been validated as good drug targets for a large variety of diseases. Trypanosoma brucei PDEB1 (TbrPDEB1) has been designated as a promising drug target for the treatment of human African trypanosomiasis. Recently, the first class of selective nanomolar TbrPDEB1 inhibitors was obtained by targeting the parasite specific P-pocket. However, these biphenyl-substituted tetrahydrophthalazinone-based inhibitors did not show potent cellular activity against Trypanosoma brucei (T. brucei) parasites, leaving room for further optimization. Herein, we report the discovery of a new class of potent TbrPDEB1 inhibitors that display improved activities against T. brucei parasites. Exploring different linkers between the reported tetrahydrophthalazinone core scaffold and the amide tail group resulted in the discovery of alkynamide phthalazinones as new TbrPDEB1 inhibitors, which exhibit submicromolar activities versus T. brucei parasites and no cytotoxicity to human MRC-5 cells. Elucidation of the crystal structure of alkynamide 8b (NPD-048) bound to the catalytic domain of TbrPDEB1 shows a bidentate interaction with the key-residue Gln874 and good directionality towards the P-pocket. Incubation of trypanosomes with alkynamide 8b results in an increase of intracellular cAMP, validating a PDE-mediated effect in vitro and providing a new interesting compound series for further studies towards selective TbrPDEB1 inhibitors with potent phenotypic activity.
几种 3'，5'-环核苷酸磷酸二酯酶（PDEs）已被证实是治疗多种疾病的良好药物靶点。布氏锥虫 PDEB1（TbrPDEB1）已被确定为治疗人类非洲锥虫病的有前途的药物靶点。最近，通过靶向寄生虫特异性 P 口袋获得了第一批选择性纳摩尔 TbrPDEB1 抑制剂。然而，这些联苯取代的四氢酞嗪酮为基础的抑制剂对布氏锥虫（T. brucei）寄生虫没有表现出有效的细胞活性，为进一步优化留下了空间。在此，我们报告了一类新的有效 TbrPDEB1 抑制剂的发现，它们对 T. brucei 寄生虫的活性得到了改善。在报道的四氢酞嗪酮核心支架和酰胺尾部之间探索不同的连接基，导致发现了炔酰胺酞嗪酮作为新的 TbrPDEB1 抑制剂，其对 T. brucei 寄生虫具有亚微摩尔活性，对人 MRC-5 细胞没有细胞毒性。阐明与 TbrPDEB1 催化结构域结合的炔酰胺 8b（NPD-048）的晶体结构表明与关键残基 Gln874 形成双齿相互作用，并对 P 口袋具有良好的方向性。将炔酰胺 8b 孵育于锥虫中会导致细胞内 cAMP 增加，体外验证了 PDE 介导的作用，并提供了一个新的有趣的化合物系列，用于进一步研究具有有效表型活性的选择性 TbrPDEB1 抑制剂。
