1-[(2,3-Dihydro-1-benzofuran-2-yl) methyl]piperazines as novel anti-inflammatory compounds: Synthesis and evaluation on H3 R/H4 R

Abstract

The histamine receptors (HRs) are members of G-protein-coupled receptor superfamily and traditional targets of huge therapeutic interests. Recently, H₃ R and H₄ R have been explored as targets for drug discovery, including in the search for dual-acting H₃ R/H₄ R ligands. The H₄ R, the most recent histamine receptor, is a promising target for novel anti-inflammatory agents in several conditions such as asthma and other chronic inflammatory diseases. Due to similarity with previously reported ligands of HRs, a set of 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines were synthesized and evaluated in competitive binding assays as H₃ R/H₄ R ligands herein. The results showed the compounds presented affinity (K_i ) for H₃ R/H₄ R in micromolar range, and they are more selective to H₃ R. All the compounds showed no important cytotoxicity to mammalian cells. The phenyl-substituted compound LINS01005 has shown the higher affinity of the set for H₄ R, but no considerable selectivity toward this receptor over H₃ R. LINS01005 showed interesting anti-inflammatory activity in murine asthma model, reducing the eosinophil counts in bronchoalveolar lavage fluid, as well as the COX-2 expression. The presented compounds are valuable prototypes for further improvements to achieve better anti-inflammatory agents.

Keywords: H3R ligand; H4R ligand; anti-inflammatory agent; asthma; histamine receptor.