ABSTRACT
The intestinal barrier is the main contributor to gut homeostasis. Perturbations of the intestinal epithelium or supporting factors can lead to the development of intestinal hyperpermeability, termed "leaky gut". A leaky gut is characterized by loss of epithelial integrity and reduced function of the gut barrier, and is associated with prolonged use of Non-Steroidal Anti-Inflammatories. The harmful effect of NSAIDs on intestinal and gastric epithelial integrity is considered an adverse effect that is common to all drugs belonging to this class, and it is strictly dependent on NSAID properties to inhibit cyclo-oxygenase enzymes. However, different factors may affect the specific tolerability profile of different members of the same class. The present study aims to compare the effects of distinct classes of NSAIDs, such as ketoprofen (K), Ibuprofen (IBU), and their corresponding lysine (Lys) and, only for ibuprofen, arginine (Arg) salts, using an in vitro model of leaky gut. The results obtained showed inflammatory-induced oxidative stress responses, and related overloads of the ubiquitin-proteasome system (UPS) accompanied by protein oxidation and morphological changes to the intestinal barrier, many of these effects being counteracted by ketoprofen and ketoprofen lysin salt. In addition, this study reports for the first time a specific effect of R-Ketoprofen on the NFkB pathway that sheds new light on previously reported COX-independent effects, and that may account for the observed unexpected protective effect of K on stress-induced damage on the IEB.
Subject(s)
Ketoprofen , Humans , Ibuprofen/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Oxidative StressABSTRACT
Chemokines CXCL8 and CXCL1 play a key role in the recruitment of neutrophils at the site of inflammation. CXCL8 binds two membrane receptors, CXCR1 and CXCR2, whereas CXCL1 is a selective agonist for CXCR2. In the past decade, the physiopathological role of CXCL8 and CXCL1 has been investigated. A novel class of small molecular weight allosteric CXCR1 inhibitors was identified, and reparixin, the first drug candidate, is currently under clinical investigation in the prevention of ischemia/reperfusion injury in organ transplantation. Reparixin binding mode to CXCR1 has been studied and used for a computer-assisted design program of dual allosteric CXCR1 and CXCR2 inhibitors. In this paper, the results of modeling-driven SAR studies for the identification of potent dual inhibitors are discussed, and three new compounds (56, 67, and 79) sharing a common triflate moiety have been selected as potential leads with optimized pharmacokinetic characteristics.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Interleukin-8/antagonists & inhibitors , Mesylates/chemical synthesis , Phenylpropionates/chemical synthesis , Propionates/chemical synthesis , Receptors, Interleukin-8A/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Allosteric Regulation , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Chemotaxis, Leukocyte , Dinoprostone/biosynthesis , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/physiology , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/metabolism , Mesylates/chemistry , Mesylates/pharmacology , Mice , Models, Molecular , Mutation , Phenylpropionates/chemistry , Phenylpropionates/pharmacology , Propionates/pharmacokinetics , Propionates/pharmacology , Receptors, Interleukin-8A/genetics , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The unusual reactivity of 1-phenyl-1-ethanesulfonic acid in thionyl chloride was investigated. Mechanistic considerations led us to set up a new and efficient synthesis of E-arylethenesulfonamides starting from 1-hydroxy-1-arylalkanes. The easy availability of the starting materials and the straightforward, one-pot procedure make this process an attractive method for the preparation of these compounds currently largely employed in chemical and pharmaceutical fields.
