Chemical Biology and Drug Design
Chemical Biology and Drug Design
4 years ago

1-[(2,3-Dihydro-1-benzofuran-2-yl) methyl]piperazines as novel anti-inflammatory compounds: Synthesis and evaluation on H3R/H4R

1-[(2,3-Dihydro-1-benzofuran-2-yl) methyl]piperazines as novel anti-inflammatory compounds: Synthesis and evaluation on H3R/H4R
Aleksandro Martins Balbino, João Paulo dos Santos Fernandes, Lanfranco Ranieri Paolo Troncone, Ana Claudia Torrecilhas, Michelle Fidelis Corrêa, Richardt Gama Landgraf, Marina Themoteo Varela
The histamine receptors (HRs) are members of G-protein-coupled receptor superfamily and traditional targets of huge therapeutic interests. Recently, H3R and H4R have been explored as targets for drug discovery, including in the search for dual-acting H3R/H4R ligands. The H4R, 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 H3R/H4R ligands herein. The results showed the compounds presented affinity (Ki) for H3R/H4R in micromolar range, and they are more selective to H3R. All the compounds showed no important cytotoxicity to mammalian cells. The phenyl-substituted compound LINS01005 has shown the higher affinity of the set for H4R, but no considerable selectivity toward this receptor over H3R. 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. Histamine H3R and H4R receptors have been explored as targets for drug discovery. We present herein four non-cytotoxic compounds with moderate affinity for these targets. The compound LINS01005 has shown promising anti-inflammatory activity in murine asthma model.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.12947

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