Search for histamine H4 receptor ligands in the group of 4-methylpiperazino amide derivatives

Abstract

Histamine fulfils its important role in a large number of physiological and pathological processes by acting through a group of four G-protein coupled histamine receptor subtypes: (H1–H4). Human histamine H4 receptor (hH4R) was recently discovered independently by several research groups [1, 2]. The hH4R shares some homology to the histamine H3 receptor and is preferentially expressed on the hematopoietic and immune cells (basophils, eosinophils, mast cells and dendritic T cells), suggesting a role in inflammatory and immunological processes [2, 3]. H4R ligands may, therefore, provide a novel therapeutic approach to the treatment of immune diseases [3, 4]. JNJ 7777120 (1-[(5-Chloro-1H-indol-2-yl)carbonyl]4-methylpiperazine) is a well known high affinity antagonist of hH4R [5], which was shown to posses at least 1,000-fold selectivity over H1, H2 or H3 receptors. In our research, the 4-methylpiperazino amide part of JNJ 7777120 was considered as a basis in the design of the novel structures. Taking into account the structural analogy, it can be assumed that other 4-methylpiperazino amide derivatives would exhibit similar pharmacological features.