The novel phospho‐non‐steroidal anti‐inflammatory drugs, OXT‐328, MDC‐22 and MDC‐917, inhibit adjuvant‐induced arthritis in rats

Abstract

BACKGROUND AND PURPOSEThe use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of rheumatoid arthritis (RA) is limited by their toxicity. We evaluated the anti-inflammatory efficacy and safety of three novel modified NSAIDs, phospho-aspirin, phospho-ibuprofen and phospho-sulindac. EXPERIMENTAL APPROACHWe determined the anti-inflammatory effects and gastrointestinal safety of the phospho-NSAIDs in the rat adjuvant arthritis model and studied their mechanism of action in cultured cells, Cytokines were measured with ELISA and activation of nuclear factor-kB (NF-kB) by immunohistochemistry. KEY RESULTSAll three phospho-NSAIDs showed less gastrointestinal toxicity than their parent compounds and demonstrated strong anti-inflammatory effects, essentially reversing joint inflammation and oedema. They have a broad but not uniform effect on the expression of relevant cytokines, in general decreasing IL-6 and IL-1b and increasing IL-10 levels in rat plasma and cultured cells. Phospho-sulindac and phospho-ibuprofen but not phospho-aspirin suppressed PGE2 production in vitro, whereas phospho-aspirin (in contrast to aspirin) showed the same effect in vivo. In joint tissues, phospho-aspirin inhibited NF-kB activation, and suppressed inflammation and bone resorption. Phospho-aspirin also inhibited Jurkat T cell proliferation. In general, phospho-aspirin had greater efficacy but different effects upon inflammatory mediators compared with aspirin. The chemical modification of the parent NSAIDs seems crucial for their safety and efficacy. CONCLUSIONS AND IMPLICATIONSPhospho-aspirin, phospho-ibuprofen and phospho-sulindac were safer than their parent NSAIDs, were highly effective in rat adjuvant arthritis and inhibited many key mediators in the pathophysiology of RA. These novel compounds are promising candidate drugs for the treatment of RA and merit further evaluation. AbbreviationsBrdU, 5-bromo-2′-deoxyuridine; FA, Freund's adjuvant; LPS, lipopolysaccharide; NF-kB, nuclear factor-kB; NSAID, non-steroidal anti-inflammatory drug; RA, rheumatoid arthritis BJP British Journal of Pharmacology

Phospho-Ibuprofen (MDC-917) Is a Novel Agent against Colon Cancer: Efficacy, Metabolism, and Pharmacokinetics in Mouse Models

“…The jpet.aspetjournals.org differences in efficacy between the two were statistically not significant; such lack of significance is probably caused by a lack of power. Nonetheless, we deem these differences as clinically relevant, especially when the greater safety of PI is factored in (current data and Huang et al, 2011).…”

“…1, inset). PI has strong antiinflammatory properties both in vitro and in animal models of arthritis, and it was shown to have far better gastrointestinal safety than conventional ibuprofen (Huang et al, 2011). PI inhibited cancer cell growth 16 to 23 times more potently than its parent drug, ibuprofen.…”

A Novel Ras Inhibitor (MDC-1016) Reduces Human Pancreatic Tumor Growth in Mice

“…PFTS was generated by modifying the carboxylic group of FTS to enhance its efficacy, as we have done with other anticancer agents [20][21][22]26,32,33]. PFTS has a higher capacity to inhibit Ras activity and is more effective than FTS in suppressing pancreatic cancer cell growth.…”

“…Goldberg et al have shown that modifications of the FTS carboxylic group by esterification or amidation yield compounds with improved growth inhibitory activity compared to FTS [19]. We have also demonstrated that covalent modifications of several carboxylic nonsteroidal antiinflammatory drugs generate compounds of superior efficacy and safety [20][21][22]. With this in mind, we synthesized the novel phospho-FTS (PFTS; MDC-1016), following the formula FTS-butane-diethyl phosphate ( Figure 1A).…”

Synthesis and Anticancer Activities of 4-[(Halophenyl)diazenyl]phenol and 4-[(Halophenyl)diazenyl]phenyl Aspirinate Derivatives against Nasopharyngeal Cancer Cell Lines

“…The modification of pharmacologically active compounds may lead to a new finding of novel drugs with diverse pharmacological activities [8]. Chemical modification of aspirin, for instance, has been reported to reduce gastrointestinal toxicity and exhibited diverse biological activities such as anticancer [9], antiinflammatory [10], and antibacterial [11,12] activities. Aspirin 2 Journal of Chemistry bearing active functional groups such as diethyl phosphate and nitro groups has been reported to have anticancer activity against pancreatic and colon cancers [13,14].…”