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, H R and H R have been explored as targets for drug discovery, including in the search for dual-acting H R/H R ligands. The H 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 R/H R ligands herein. The results showed the compounds presented affinity (K ) for H R/H R in micromolar range, and they are more selective to H 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 R, but no considerable selectivity toward this receptor over H 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.

Pharmacological andSARanalysis of theLINS01 compounds at the human histamine H1, H2, and H3receptors

“…The LINS01 compounds ( 1a – 1i ) were synthesized as previously reported by our group (Figure , see Supporting Information). In case of the nonsubstituted phenols (to obtain compounds 1a – d ), the commercial 2‐allylphenol was used as starting material. In case of R′‐substituted molecules, the corresponding phenols 2e – h were used as starting material, which was allylated with allyl bromide in conventional or ultrasonic conditions, with good to excellent yields.…”

“…indeed, then comprising the green chemistry principles . The spectroscopic data for the final compounds (see Supporting Information) and intermediates are in accordance with the literature reports . None of the LINS01 molecules were previously evaluated in H 1 R and H 2 R, and the compound 1i was not evaluated in H 3 R before.…”

“…Initial studies examining [ 3 H]‐histamine binding to H 3 R and H 4 R membrane preparations of the first four compounds suggested micromolar affinities for these compounds, with higher affinity for the H 3 R than H 4 R . A further study of other LINS01 compounds in HEK293 cells transiently expressing the H 3 R or H 4 R suggested the LINS01 compounds are antagonists or weak inverse agonists but once again that they had a higher affinity for the H 3 R than the H 4 R .…”

“…As the LINS01 molecules were originally designed to be similar to the H 4 R selective antagonist JNJ‐7777120, it was expected that these molecules would also be H 4 ‐selective. Indeed, two molecules (LINS01005— 1d and LINS01007— 1e ) appear to have a dose‐dependent anti‐inflammatory effect in a murine mouse model of asthma that correlated with the H 4 R affinity . However, these studies have also shown that most of LINS01 molecules actually have a higher affinity for the H 3 R than the H 4 R .…”

“…Indeed, two molecules (LINS01005— 1d and LINS01007— 1e ) appear to have a dose‐dependent anti‐inflammatory effect in a murine mouse model of asthma that correlated with the H 4 R affinity . However, these studies have also shown that most of LINS01 molecules actually have a higher affinity for the H 3 R than the H 4 R . It was therefore important to know the pharmacological profile of these compounds for the human H 1 R and H 2 R.…”