TY - JOUR
T1 - NO-NSAIDs. Part 3
T2 - Nitric oxide-releasing prodrugs of non-steroidal anti-inflammatory drugs
AU - Borhade, Namdev
AU - Pathan, Asif Rahimkhan
AU - Halder, Somnath
AU - Karwa, Manoj
AU - Dhiman, Mini
AU - Pamidiboina, Venu
AU - Gund, Machhindra
AU - Deshattiwar, Jagannath Janardhan
AU - Mali, Sunil Vasantrao
AU - Deshmukh, Nitin Janardanrao
AU - Senthilkumar, Subrayan Palanisamy
AU - Gaikwad, Parikshit
AU - Tipparam, Santhosh Goud
AU - Mudgal, Jayesh
AU - Dutta, Milan Chandra
AU - Burhan, Aslam Usmangani
AU - Thakre, Gajanan
AU - Sharma, Ankur
AU - Deshpande, Shubhada
AU - Desai, Dattatraya Chandrakant
AU - Dubash, Nauzer Pervez
AU - Jain, Arun Kumar
AU - Sharma, Somesh
AU - Nemmani, Kumar Venkata Subrahmanya
AU - Satyam, Apparao
PY - 2012/4/1
Y1 - 2012/4/1
N2 - 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 E 2 (PGE 2) 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.
AB - 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 E 2 (PGE 2) 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.
UR - https://www.scopus.com/pages/publications/84859478522
UR - https://www.scopus.com/pages/publications/84859478522#tab=citedBy
U2 - 10.1248/cpb.60.465
DO - 10.1248/cpb.60.465
M3 - Article
C2 - 22466730
AN - SCOPUS:84859478522
SN - 0009-2363
VL - 60
SP - 465
EP - 481
JO - Chemical and Pharmaceutical Bulletin
JF - Chemical and Pharmaceutical Bulletin
IS - 4
ER -