Design, synthesis and biological evaluation of novel NO-releasing NSAIDs possessing a N-diazen-1-ium-1,2-diolate (NONOate), which offers additional advantages compared with organic nitrate-based NO-NSAIDs

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most useful clinical therapies for the treatment of pain, fever and inflammation. It is estimated that more than 30 million people take NSAIDs every day. However, the major mechanism by which NSAIDs exert their anti- inflammatory activity is also responsible for the gastrointestinal, renal and hepatic side effects observed in patients undergoing long-term treatment of chronic conditions. The most common side effects associated with NSAID administration are gastroduodenal erosions and ulcerations affecting around 15% of chronic NSAID users. While many of these clinical manifestations are mild, they may develop into serious events such as bleeding, perforation, obstruction, and sudden death. Therefore, the gastric irritant effect of NSAIDs (particularly aspirin) can be a deterrent to its long-term use for the prophylactic prevention of adverse cardiovascular events such as stroke and myocardial infarction, or as a safe chemopreventive agent to avoid the recurrence of colorectal cancer (CRC). One of the main strategies that have emerged to improve the safety profile of NSAIDs is the linkage of a nitric oxide (NO)-releasing moiety to the structure of classical NSAIDs (NO-NSAIDs). However, all NO-releasing NSAIDs published so far have a nitrooxyalkyl group as the NO-releasing group. An important drawback to this design is the fact that production of NO (only one equivalent) from organic nitrate esters requires a metabolic three-electron reduction in vivo, and this activation decreases in efficiency on continued use of the drugs, contributing to "nitrate tolerance". This invention describes the design, synthesis and biological evaluation of novel NO-releasing non-steroidal anti-inflammatory prodrugs (NONO-NSAIDs) possessing a N- diazen-1-ium-1,2-diolate (NONOate), which offers additional advantages compared with organic nitrate-based NO-NSAIDs: (a) Simultaneous release of the corresponding NSAID and NO; (b) Production of two equivalents of NO (twice as much) by a first-order rate; (c) Metabolic activation (hydrolysis) mediated by non-specific esterases, which unlike redox metabolism, is not expected to produce tolerance upon long- term treatment. Applications: This invention provides a group of anti- inflammatory, analgesic, and gastrointestinal safe prodrugs, which are expected to be a suitable alternative for the prophylactic prevention of adverse cardiovascular events such as stroke and myocardial infarction, as well as cancer chemoprevention. Market: An estimated 60 million people in the United States use NSAIDs regularly; An estimated $5 billion are spent each year in the United States on prescription NSAIDs and approximately $2 billion are spent on over-the-counter NSAIDs Development Status: Pre-clinical data is available Related Publication: C Velazquez, PN Praveen Rao, EE Knaus. Novel nonsteroidal anti-inflammatory drugs possessing a nitric oxide donor diazen-1-ium-1,2-diolate moiety: design, synthesis, biological evaluation, and nitric oxide release studies. J Med Chem. 2005 Jun16;48(12):4061-4067.

Preclinical

U.S. Provisional Application 60/794,421 filed 24 Apr 2006 (HHS Reference No. E-186-2006/0-US-01) Inventors: Carlos Velazquez Martinez (NCI) et al.

Licensees Sought: Available for exclusive and non-exclusive licensing. Collaborative Research Opportunity: The Chemistry Section of the Laboratory of Comparative Carcinogenesis is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the prodrugs described, as new and safer analgesic, anti-inflammatory, anti-thrombotic, and cancer chemopreventive agents. Please contact Betty Tong, Ph.D. at 301-594-4263 or tongb@mail.nih.gov for more information.