Anticancer Activity and Mechanisms of Action of MAPK pathway inhibitors


Proc. injury or inflammation. Chronic ongoing extracellular SK1-IN-1 release of cytotoxic enzymes permanently damages host tissues, playing a pivotal role in the pathogenesis of severe asthma and COPD. Due to their prominent role in numerous inflammatory diseases, one strategy to prevent or mitigate the severity of disease progression is to block the migration of PMNs to sites of inflammation.2 The ability of PMNs to migrate towards sites of injury or inflammation is known as chemotaxis, and is directed in large part by the Cys-Xaa-Cys (CXC) chemokine receptors CXCR1 and CXCR2. The endogenous ligands for these G-protein coupled receptors (GPCRs) include growth-related oncogene (GRO, or CXCL1) and interleukin-8 (IL8, or CXCL8).3 Development of small molecule antagonists of CXCR2 is a major focus of contemporary pharmaceutical research.4,5 Reparixin 1 (Determine 1) is a ketoprofen derivative being investigated in trials for the prevention and treatment of delayed graft function and pancreatic islet transplantation.6,7 In 1998, the first PDGFA small molecule CXCR2 antagonist based on the diaryl urea pharmacophore was reported.8 Open in a separate window Determine 1 Chemokine antagonists Danirixin 2 is a diaryl urea CXCR2 antagonist being developed for the treatment of pulmonary diseases, including COPD.9 The central urea motif in the diarylureas was later replaced with the cyclic urea bioisostere 3,4-diaminocyclobut-3-ene-1,2-dione to provide SK1-IN-1 potent analogues as represented by navarixin 3.10 In recent clinical evaluation, navarixin inhibited ozone inhalation-induced sputum PMN recruitment in healthy subjects.11 AZD-5069 4 is a CXCR2 antagonist whose structure was only recently disclosed.12 AZD-5069 is being developed for the treatment of moderate to severe COPD.13 Recent publications detailing the development of novel antagonists from the Neamati group14,15 and Novartis16,17 as well as continued activity in the patent literature,18 underscore the continued interest in developing CXCR2 antagonists for inflammatory diseases. Based on the known roles of CXCR1/2 in PMN chemotaxis and function, we hypothesized that dual blockade of CXCR1 and CXCR2 would provide critical therapeutic benefit to patients suffering from pulmonary inflammatory diseases and began a discovery program to identify and develop dual CXCR1/2 antagonists. The discovery and evaluation of the first reported boronic acid made up of CXCR1/2 antagonist 5 (SX-517) was previously reported.19 Compound 5 belongs to the nicotinamide class of allosteric CXCR1/2 antagonists, which act via an intracellular mechanism of action20 and are unable to displace IL8 binding.19 Although 5 exhibited anti-inflammatory activity em in vivo /em , further preclinical development was hindered by its metabolic instability. A focused SAR SK1-IN-1 effort to increase metabolic stability was then undertaken. A major product of metabolic degradation was the result of oxidative deboronylation of 5 to yield the corresponding 2-hydroxy derivative. It was hypothesized that appropriate derivitization would hinder oxidative cleavage of the boronic acid, thereby increasing both metabolic stability and systemic exposure upon administration. From these efforts, the chemokine antagonist 6 was discovered. Herein the SAR can be reported by us research that resulted in the finding of substance 6, a thionicotinamide derivative that displays increased metabolic balance while retaining potent activity at both CXCR2 and CXCR1 receptors. Substance 6 was examined inside a rat style of pulmonary swelling additional, and simulated receptor SK1-IN-1 docking research were performed to help expand understand the system of action because of this exclusive course of allosteric CXCR1/2 antagonists. Synthesis from the examined compounds was accomplished as demonstrated in Structure 1. Thionicotinamide 719 (1 eq.) as well as the related bromomethyl derivative (1 eq.) had been dissolved in anhydrous dimethylformamide (2 ml/mmol) within an range dried round bottom level flask. To the perfect solution is, triethylamine (1 eq) was added, as well as the response was permitted to continue at room temp. The reaction progress was monitored by either LC-MS or TLC.