Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago 6094411, Chile.
Bioorg Med Chem. 2019 Jul 15;27(14):3194-3200. doi: 10.1016/j.bmc.2019.05.042. Epub 2019 May 29.
Inspired by marine compounds the derivatization of the natural pyrrolo[2,3-d]pyrimidine lead scaffold led to a series of novel compounds targeting the histamine H receptor. The focus was set on improved binding towards the receptor and to establish an initial structure-activity relationship for this compound class based on the lead structure (compound V, K value of 126 nM). As highest binding affinities were found with 1,4-bipiperidines as basic part of the ligands, further optimization was focused on 4-([1,4'-bipiperidin]-1'-yl)-pyrrolo[2,3-d]pyrimidines. Related pyrrolo[2,3-d]pyrimidines that were isolated from marine sponges like 4-amino-5-bromopyrrolo[2,3-d]pyrimidine (compound III), showed variations in halogenation pattern, though in a next step the impact of halogenation at 2-position was evaluated. The chloro variations did not improve the affinity compared to the dehalogenated compounds. However, the simultaneous introduction of lipophilic cores with electron-withdrawing substitution patterns in 7-position and dehalogenation at 2-position (11b, 12b) resulted in compounds with significantly higher binding affinities (K values of 7 nM and 6 nM, respectively) than the initial lead structure compound V. The presented structures allow for a reasonable structure-activity relationship of pyrrolo[2,3-d]pyrimidines as histamine H receptor ligands and yielded novel lead structures within the natural compound library against this target.
受海洋化合物的启发，对天然吡咯并[2,3-d]嘧啶先导骨架进行了衍生化，得到了一系列针对组胺 H 受体的新型化合物。研究重点是提高化合物对受体的结合能力，并基于先导结构（化合物 V，K 值为 126 nM）建立该类化合物的初步构效关系。由于配体中碱性部分的 1,4-双哌啶基表现出最高的结合亲和力，因此进一步的优化集中在 4-([1,4'-双哌啶]-1'-基）-吡咯并[2,3-d]嘧啶上。从海洋海绵中分离出的类似 4-氨基-5-溴吡咯并[2,3-d]嘧啶（化合物 III）的吡咯并[2,3-d]嘧啶，其卤化模式有所不同，但在下一步中评估了 2 位卤化的影响。与脱卤化合物相比，氯代变体没有改善亲和力。然而，在 7 位同时引入具有吸电子取代模式的亲脂性核，并在 2 位脱卤（11b、12b），得到的化合物具有显著更高的结合亲和力（K 值分别为 7 nM 和 6 nM），比初始先导结构化合物 V 更高。所呈现的结构允许对作为组胺 H 受体配体的吡咯并[2,3-d]嘧啶进行合理的构效关系研究，并为该靶标提供了天然化合物库中的新型先导结构。
