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1‐[(2,3‐Dihydro‐1‐benzofuran‐2‐yl) methyl]piperazines as novel anti‐inflammatory compounds: Synthesis and evaluation on H 3 R/H 4 R
Author(s) -
Corrêa Michelle Fidelis,
Varela Marina Themoteo,
Balbino Aleksandro Martins,
Torrecilhas Ana Claudia,
Landgraf Richardt Gama,
Troncone Lanfranco Ranieri Paolo,
Fernandes João Paulo dos Santos
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12947
Subject(s) - chemistry , cytotoxicity , receptor , stereochemistry , histamine receptor , histamine , selectivity , pharmacology , biochemistry , in vitro , biology , antagonist , catalysis
The histamine receptors (HRs) are members of G‐protein‐coupled receptor superfamily and traditional targets of huge therapeutic interests. Recently, H 3 R and H 4 R have been explored as targets for drug discovery, including in the search for dual‐acting H 3 R/H 4 R ligands. The H 4 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 H 3 R/H 4 R ligands herein. The results showed the compounds presented affinity ( K i ) for H 3 R/H 4 R in micromolar range, and they are more selective to H 3 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 H 4 R, but no considerable selectivity toward this receptor over H 3 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.