New lead elements for histamine H-3 receptor ligands in the pyrrolo[2,3-d] pyrimidine class

作者：Espinosa Bustos Christian^*; Frank Annika; Arancibia Opazo Sandra; Salas Cristian O; Fierro Angelica; Stark Holger

来源：Bioorganic & Medicinal Chemistry Letters, 2018, 28(17): 2890-2893.

DOI：10.1016/j.bmcl.2018.07.023

• Histamine H-3 receptor
• Pyrrolo[2,3-d]pyrimidine derivatives
• Microwave assisted synthesis
• G-protein coupled receptors

This work describes the microwave assisted synthesis of twelve novel histamine H-3 receptor ligands. They display pyrrolo [2,3-d]pyrimidine derivatives with rigidized aliphatic amines as warheads. The compounds were screened for H3R and H4R binding affinities in radioligand displacement assays and the most potent compounds were evaluated for H3R binding properties in vitro and in docking studies. The combination of a rigidized H3R warhead and the pyrrolo[2,3-d]pyrimidine scaffold resulted in selective activity at the H-3 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-3 receptor ligands.

• 出版日期2018-9-15