Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems , Vrije Universiteit Amsterdam , 1081 HZ Amsterdam , The Netherlands.
School of Biosciences , University of Kent , Canterbury CT2 7NJ , U.K.
J Med Chem. 2018 May 10;61(9):3870-3888. doi: 10.1021/acs.jmedchem.7b01670. Epub 2018 May 1.
Several trypanosomatid cyclic nucleotide phosphodiesterases (PDEs) possess a unique, parasite-specific cavity near the ligand-binding region that is referred to as the P-pocket. One of these enzymes, Trypanosoma brucei PDE B1 (TbrPDEB1), is considered a drug target for the treatment of African sleeping sickness. Here, we elucidate the molecular determinants of inhibitor binding and reveal that the P-pocket is amenable to directed design. By iterative cycles of design, synthesis, and pharmacological evaluation and by elucidating the structures of inhibitor-bound TbrPDEB1, hPDE4B, and hPDE4D complexes, we have developed 4a,5,8,8a-tetrahydrophthalazinones as the first selective TbrPDEB1 inhibitor series. Two of these, 8 (NPD-008) and 9 (NPD-039), were potent ( K = 100 nM) TbrPDEB1 inhibitors with antitrypanosomal effects (IC = 5.5 and 6.7 μM, respectively). Treatment of parasites with 8 caused an increase in intracellular cyclic adenosine monophosphate (cAMP) levels and severe disruption of T. brucei cellular organization, chemically validating trypanosomal PDEs as therapeutic targets in trypanosomiasis.
几种利什曼原虫环核苷酸磷酸二酯酶（PDEs）在靠近配体结合区域的地方具有一个独特的、寄生虫特异性的腔，称为 P 口袋。其中一种酶，即布氏锥虫 PDE B1（TbrPDEB1），被认为是治疗非洲昏睡病的药物靶点。在这里，我们阐明了抑制剂结合的分子决定因素，并揭示了 P 口袋可进行定向设计。通过设计、合成和药理学评估的迭代循环，并阐明抑制剂结合的 TbrPDEB1、hPDE4B 和 hPDE4D 复合物的结构，我们开发了 4a,5,8,8a-四氢邻苯二甲嗪酮作为第一个选择性 TbrPDEB1 抑制剂系列。其中两种，即 8（NPD-008）和 9（NPD-039），是有效的（K = 100 nM）TbrPDEB1 抑制剂，具有抗锥虫作用（IC = 5.5 和 6.7 μM）。用 8 处理寄生虫会导致细胞内环腺苷酸（cAMP）水平升高和 T. brucei 细胞结构严重破坏，这从化学上验证了锥虫 PDEs 是锥虫病的治疗靶点。
