2nd -Generation, NO-Releasing Non-Steroidal Anti-Inflammatory Prodrugs

Background:
The Laboratory of Comparative Carcinogenesis at the National Cancer Institute is seeking statements of capability, or interest, from parties interested in collaborative research to further develop, evaluate, and/or commercialize new and safer analgesic, anti-inflammatory, anti-thrombotic, and cancer chemopreventive agents.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most useful clinical therapies for the treatment of pain, fever, and inflammation. An estimated 60 million people in the United States use NSAIDs regularly. Despite their popularity of NSAIDS, there has been increasing safety concerns regarding the long-term use of NSAIDs. The most common side effects associated with NSAID administration are gastroduodenal erosions and ulcerations affecting around 15% of chronic NSAID users.

Technology:
This invention describes the design, synthesis and biological evaluation of novel NO-releasing, non-steroidal anti-inflammatory prodrugs possessing a N-diazen-1-ium-1,2-diolate (NONO-NSAIDs). This approach is conceptually different than organic nitrate-based NO-NSAIDs, offering improvements and advantages such as:

• Simultaneous release of the corresponding NSAID and nitric oxide (NO).
• Production of two equivalents of NO (twice as much) by a first-order rate.
• Reliable metabolic activation requiring a simple ester hydrolysis which unlike redox metabolism, is not expected to produce tolerance upon long-term treatment.

IP Status:
A U.S. Provisional Application was filed in April 2006.

R&D Status:
Pre-clinical; proof-of-concept completed.

Follow-on R&D:

• Preclinical toxicity.
• Ulcerogenicity assays (larger group of animals).
• Pharmacokinetic assays in vitro (incubation with cells and tissues, cell extracts, etc.)
• Anti-inflammatory activity

Value Proposition:

• 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.
• Non ulcerogenic analgesic and anti-inflammatory drugs.

Contact Information:
John D. Hewes, Ph.D., NCI Technology Transfer Center
Phone: 301-435-3121
E-mail: Hewesj@mail.nih.gov

Reference:  #499 NR

Updated 10/29/2007