Espinosa-Bustos Christian, Frank Annika, Arancibia-Opazo Sandra, Salas Cristian O, Fierro Angelica, Stark Holger
Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Santiago 6094411, Chile.
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitaetsstr. 1, 40225 Düsseldorf, Germany.
Bioorg Med Chem Lett. 2018 Sep 15;28(17):2890-2893. doi: 10.1016/j.bmcl.2018.07.023. Epub 2018 Jul 17.
This work describes the microwave assisted synthesis of twelve novel histamine H receptor ligands. They display pyrrolo[2,3-d]pyrimidine derivatives with rigidized aliphatic amines as warheads. The compounds were screened for HR and HR binding affinities in radioligand displacement assays and the most potent compounds were evaluated for HR binding properties in vitro and in docking studies. The combination of a rigidized HR warhead and the pyrrolo[2,3-d]pyrimidine scaffold resulted in selective activity at the H receptor with a pK value of 6.90 for the most potent compound. A bipiperidine warhead displayed higher affinity than a piperazine or morpholine motif, while a naphthyl moiety in the arbitrary region increased affinity compared to a phenyl derivative. The compounds can be starting points for novel, simply synthesized histamine H receptor ligands.
这项工作描述了十二种新型组胺H受体配体的微波辅助合成。它们展示了以刚性脂肪胺作为弹头的吡咯并[2,3-d]嘧啶衍生物。在放射性配体置换试验中筛选这些化合物的H1和H2受体结合亲和力，并对最有效的化合物进行体外和对接研究的H1受体结合特性评估。刚性化的H1弹头与吡咯并[2,3-d]嘧啶支架的结合导致在H1受体上具有选择性活性，最有效化合物的pK值为6.90。双哌啶弹头显示出比哌嗪或吗啉基序更高的亲和力，而任意区域中的萘基部分与苯基衍生物相比增加了亲和力。这些化合物可以作为新型、简单合成的组胺H受体配体的起点。
