title: 1-[(2,3-Dihydro-1-benzofuran-2-yl) methyl]piperazines as novel anti-inflammatory compounds: Synthesis and evaluation on H3R/H4R.
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 (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.
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP, Brazil.
authors.forename: Michelle Fidelis
authors.initials: MF
authors.lastname: Corrêa
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP, Brazil.
authors.forename: Marina Themoteo
authors.initials: MT
authors.lastname: Varela
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP, Brazil.
authors.forename: Aleksandro Martins
authors.initials: AM
authors.lastname: Balbino
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP, Brazil.
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Torrecilhas
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP, Brazil.
authors.forename: Richardt Gama
authors.initials: RG
authors.lastname: Landgraf
authors.affiliation: Instituto Butantan, São Paulo, SP, Brazil.
authors.forename: Lanfranco Ranieri Paolo
authors.initials: LRP
authors.lastname: Troncone
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP, Brazil.
authors.forename: João Paulo Dos Santos
authors.identifier: 0000-0002-9089-273X
authors.initials: JPDS
authors.lastname: Fernandes
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000276:immunology; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000276:immunology*; D011968:Receptors, Histamine / Q000276:immunology*; D018100:Receptors, Histamine H3 / Q000276:immunology*; D000074040:Receptors, Histamine H4
chemical_list: C507249:1-benzofuran; D000893:Anti-Inflammatory Agents; D001572:Benzofurans; C418607:HRH4 protein, human; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4
keywords: H3R ligand; H4R ligand; anti-inflammatory agent; asthma; histamine receptor