title: NO-NSAIDs. Part 3: nitric oxide-releasing prodrugs of non-steroidal anti-inflammatory drugs.
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 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.
authors.affiliation: Medicinal Chemistry Division, Piramal Life Sciences Limited.
authors.forename: Namdev
authors.initials: N
authors.lastname: Borhade
authors.forename: Asif Rahimkhan
authors.initials: AR
authors.lastname: Pathan
authors.forename: Somnath
authors.initials: S
authors.lastname: Halder
authors.forename: Manoj
authors.initials: M
authors.lastname: Karwa
authors.forename: Mini
authors.initials: M
authors.lastname: Dhiman
authors.forename: Venu
authors.initials: V
authors.lastname: Pamidiboina
authors.forename: Machhindra
authors.initials: M
authors.lastname: Gund
authors.forename: Jagannath Janardhan
authors.initials: JJ
authors.lastname: Deshattiwar
authors.forename: Sunil Vasantrao
authors.initials: SV
authors.lastname: Mali
authors.forename: Nitin Janardanrao
authors.initials: NJ
authors.lastname: Deshmukh
authors.forename: Subrayan Palanisamy
authors.initials: SP
authors.lastname: Senthilkumar
authors.forename: Parikshit
authors.initials: P
authors.lastname: Gaikwad
authors.forename: Santhosh Goud
authors.initials: SG
authors.lastname: Tipparam
authors.forename: Jayesh
authors.initials: J
authors.lastname: Mudgal
authors.forename: Milan Chandra
authors.initials: MC
authors.lastname: Dutta
authors.forename: Aslam Usmangani
authors.initials: AU
authors.lastname: Burhan
authors.forename: Gajanan
authors.initials: G
authors.lastname: Thakre
authors.forename: Ankur
authors.initials: A
authors.lastname: Sharma
authors.forename: Shubhada
authors.initials: S
authors.lastname: Deshpande
authors.forename: Dattatraya Chandrakant
authors.initials: DC
authors.lastname: Desai
authors.forename: Nauzer Pervez
authors.initials: NP
authors.lastname: Dubash
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: Jain
authors.forename: Somesh
authors.initials: S
authors.lastname: Sharma
authors.forename: Kumar Venkata Subrahmanya
authors.initials: KV
authors.lastname: Nemmani
authors.forename: Apparao
authors.initials: A
authors.lastname: Satyam
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D019540:Area Under Curve; D015195:Drug Design; D004952:Esters; D007094:Imides / Q000138:chemical synthesis / Q000737:chemistry; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004952:Esters; D007094:Imides; D011355:Prodrugs; D009569:Nitric Oxide