Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
Regular Articles
NO-NSAIDs. Part 3: Nitric Oxide-Releasing Prodrugs of Non-steroidal Anti-inflammatory Drugs
Namdev Borhade, Asif Rahimkhan Pathan, Somnath Halder, Manoj Karwa, Mini Dhiman, Venu Pamidiboina, Machhindra Gund, Jagannath Janardhan Deshattiwar, Sunil Vasantrao Mali, Nitin Janardanrao Deshmukh, Subrayan Palanisamy Senthilkumar, Parikshit Gaikwad, Santhosh Goud Tipparam, Jayesh Mudgal, Milan Chandra Dutta, Aslam Usmangani Burhan, Gajanan Thakre, Ankur Sharma, Shubhada Deshpande, Dattatraya Chandrakant Desai, Nauzer Pervez Dubash, Arun Kumar Jain, Somesh Sharma, Kumar Venkata Subrahmanya Nemmani, Apparao Satyam
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Keywords: nitric oxide-aspirin, nitric oxide-diclofenac, nitric oxide-naproxen, nitric oxide-flurbiprofen, nitric oxide-ketoprofen
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2012 Volume 60 Issue 4 Pages 465-481

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Abstract

In continuation of our efforts to discover novel nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) as potentially “Safe NSAIDs,” we report herein the design, synthesis and evaluation of 21 new NO-NSAIDs of commonly used NSAIDs such as aspirin, diclofenac, naproxen, flurbiprofen, ketoprofen, sulindac, ibuprofen and indomethacin. These prodrugs have NO-releasing disulfide linker attached to a parent NSAID via linkages such as an ester (compounds 9–16), a double ester (compounds 17–24), an imide (compounds 25–30) or an amide (compounds 31–33). Among these NO-NSAIDs, the ester-containing NO-aspirin (9), NO-diclofenac (10), NO-naproxen (11), and the imide-containing NO-aspirin (25), NO-flurbiprofen (27) and NO-ketoprofen (28) have shown promising oral absorption, anti-inflammatory activity and NO-releasing property, and also protected rats from NSAID-induced gastric damage. NO-aspirin compound 25, on further co-evaluation with aspirin at equimolar doses, exhibited comparable dose-dependent pharmacokinetics, inhibition of gastric mucosal prostaglandin E2 (PGE2) synthesis and analgesic properties to those of aspirin, but retained its gastric-sparing properties even after doubling its oral dose. These promising NO-NSAIDs could therefore represent a new class of potentially “Safe NSAIDs” for the treatment of arthritic pain and inflammation.

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© 2012 The Pharmaceutical Society of Japan
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