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

Author(s)

Correa, Michelle Fidelis ; Varela, Marina Themoteo ; Balbino, Aleksandro Martins ; Torrecilhas, Ana Claudia ; Landgraf, Richardt Gama ; Paolo Troncone, Lanfranco Ranieri ; dos Santos Fernandes, Joao Paulo

• Document type: Journal article
• Source: CHEMICAL BIOLOGY & DRUG DESIGN; v. 90, n. 2, p. 317-322, AUG 2017.
• Web of Science Citations: 6

Abstract

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 (K-i) 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. (AU)

• FAPESP's process: 13/20479-9 - Synthesis and evaluation of compounds potentially ligands of H4 receptors
• Grantee: João Paulo dos Santos Fernandes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/18897-7 - Contribution to antidepressive drug development
• Grantee: Lanfranco Ranieri Paolo Troncone
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/16564-3 - Synthesis and evaluation of activity of gibbilimbol B derivatives in Trypanosoma cruzi
• Grantee: Marina Themoteo Varela
• Support Opportunities: Scholarships in Brazil - Scientific Initiation