benzofurans and Inflammatory-Bowel-Diseases

Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats. A set of experiments evaluated the ability of FA5 to activate AMPK and to compare the efficacy of FA5 with ACA in an experimental model of colitis. The effects of FA-5, ACA, or dexamethasone were tested in rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis to assess systemic and tissue inflammatory parameters. In in vitro experiments, FA5 induced phosphorylation, and thus the activation, of AMPK, contextually to the activation of SIRT-1. In vivo, FA5 counteracted the increase in spleen weight, improved the colon length, ameliorated macroscopic damage score, and reduced TNF and MDA tissue levels in DNBS-treated rats. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. The novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy representing a promising pharmacological tool against bowel inflammation.

Topics: AMP-Activated Protein Kinases; Animals; Benzofurans; Body Weight; Cell Line; Colon; Dinitrofluorobenzene; Drug Development; Electrophoresis, Gel, Two-Dimensional; Enzyme Activators; Gene Ontology; Inflammatory Bowel Diseases; Interleukin-10; Male; Malondialdehyde; Mice; Organ Size; Phosphorylation; Rats, Sprague-Dawley; Spleen; Tumor Necrosis Factor-alpha

To develop effective therapeutics for inflammatory bowel disease (IBD), 2-benzylidene-2,3-dihydro-1H-inden-1-one and benzofuran-3(2H)-one derivatives, were designed and synthesized and their structure-activity relationships (SAR) were investigated. Compounds 7, 25, 26, 32, 39, 41, 52, 54, and 55 showed potent inhibitory effect (>70%) on the TNF-α-induced adhesion of monocytes to colon epithelial cells, which is one of the hallmark events leading to IBD. Such inhibitory activity of the compounds correlated with their suppressive activities against the TNF-α-induced production of ROS; ICAM-1 and MCP-1 expression, critical molecules involved in monocyte-epithelial adhesion; and NF-κB transcriptional activity. In addition, compounds 41 and 55 significantly suppressed the lipopolysaccharide (LPS)-induced expression of the TNF-α gene, with compound 55 showing better efficacy. This inhibition of TNF-α expression by compounds 41 and 55 corresponded to their additional inhibitory activity against AP-1 transcriptional activity, which is another transcription factor required for high level TNF-α expression. The strong inhibitory activity of compound 55 against an in vivo colitis model was confirmed by its dose-dependent inhibitory activity in a rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis, demonstrating compound 55 as a new potential candidate for the development of therapeutics against IBD.

Topics: Animals; Benzofurans; Colitis; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Female; HT29 Cells; Humans; Indenes; Inflammatory Bowel Diseases; Molecular Structure; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Transcription Factor AP-1; Trinitrobenzenesulfonic Acid; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; U937 Cells

Despite being a mainstay of inflammatory bowel disease (IBD) therapy, glucocorticoids (GCs) still carry significant risks with respect to unwanted side effects. Alternative drugs with a more favorable risk/benefit ratio than common GCs are thus highly desirable for the management of IBD. New and supposedly selective glucocorticoid receptor (GR) agonists (SEGRAs), with dissociated properties, have been described as promising candidates for circumventing therapeutic problems while still displaying full beneficial anti-inflammatory potency. Here, we report on compound A [CpdA; (2-((4-acetophenyl)-2-chloro-N-methyl)ethylammonium-chloride)] and N-(4-methyl-1-oxo-1H-2,3-benzoxazine-6-yl)-4-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-2-(trifluoromethyl)-4-methylpentanamide (ZK216348), two GR agonists for the treatment of experimental colitis. Their therapeutic and anti-inflammatory effects were tested in the acute trinitrobenzene sulfonic acid-mediated colitis model in mice against dexamethasone (Dex). In addition to their influence on immunological pathways, a set of possible side effects, including impact on glucose homeostasis, steroid resistance, and induction of apoptosis, was surveyed. Our results showed that, comparable with Dex, treatment with CpdA and ZK216348 reduced the severity of wasting disease, macroscopic and microscopic damage, and colonic inflammation. However, both SEGRAs exhibited no GC-associated diabetogenic effects, hypothalamic pituitary adrenal axis suppression, or development of glucocorticoid resistance. In addition, CpdA and ZK216348 showed fewer transactivating properties and successfully dampened T helper 1 immune response. Unlike ZK216348, the therapeutic benefit of CpdA was lost at higher doses because of toxic apoptotic effects. In conclusion, both SEGRAs acted as potent anti-inflammatory agents with a significantly improved profile compared with classic GCs. Although CpdA revealed a narrow therapeutic window, both GR agonists might be seen as a starting point for a future IBD treatment option.

Topics: Acute Disease; Animals; Benzofurans; Benzoxazines; Caco-2 Cells; Cells, Cultured; Colitis; HEK293 Cells; Humans; Inflammatory Bowel Diseases; Male; Mice; Mice, Inbred BALB C; Receptors, Glucocorticoid; Treatment Outcome; Trinitrobenzenesulfonic Acid