Second Generation Nitric Oxide-releasing Non-steroidal Anti-inflammatory Drugs Possessing a Diazeniumdiolate Group (NONO-NSAIDs)
Posted Jun 15 2010 5:00pm
Description of Invention: 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:
Simultaneous release of the corresponding NSAID and NO.
Production of two equivalents of NO (twice as much) by a first-order rate.
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.
Development Status: Pre-clinical data is available
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. [ PubMed abs ]
Licensing Status: 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 John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.
Portfolios: Cancer Cancer - Other Internal Medicine Internal Medicine - Therapeutics In-vitro Data
For Additional Information Please Contact: Steven Standley Ph.D. NIH Office of Technology Transfer 6011 Executive Blvd. Suite 325, Rockville, MD 20852 United States Email: sstand@mail.nih.gov Phone: 301-435-4074 Fax: 301-402-0220
Description of Invention:
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:
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.
Development Status:
Pre-clinical data is available
Inventors:
Carlos A Velazquez (NCI)
Patent Status:
HHS, Reference No. E-186-2006/0
US, Application No. 12/298,322 filed 24 Oct 2008
Relevant Publication:
Licensing Status:
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 John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.
Portfolios:
Cancer
Cancer - Other
Internal Medicine
Internal Medicine - Therapeutics
In-vitro Data
For Additional Information Please Contact:
Steven Standley Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Email: sstand@mail.nih.gov
Phone: 301-435-4074
Fax: 301-402-0220
Ref No: 1471
Updated: 06/2010