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 DesaiNauzer Pervez Dubash, Arun Kumar Jain, Somesh Sharma, Kumar Venkata Subrahmanya Nemmani, Apparao Satyam

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)465-481
Number of pages17
JournalChemical and Pharmaceutical Bulletin
Volume60
Issue number4
DOIs
Publication statusPublished - 01-04-2012

Fingerprint

Prodrugs
Non-Steroidal Anti-Inflammatory Agents
Nitric Oxide
Anti-Inflammatory Agents
Imides
Aspirin
Flurbiprofen
Ketoprofen
Stomach
Esters
Pharmaceutical Preparations
Diclofenac
Sulindac
Naproxen
Pharmacokinetics
Ibuprofen
Prostaglandins E
Amides
Indomethacin
Disulfides

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Drug Discovery

Cite this

Borhade, N., Pathan, A. R., Halder, S., Karwa, M., Dhiman, M., Pamidiboina, V., ... Satyam, A. (2012). NO-NSAIDs. Part 3: Nitric oxide-releasing prodrugs of non-steroidal anti-inflammatory drugs. Chemical and Pharmaceutical Bulletin, 60(4), 465-481. https://doi.org/10.1248/cpb.60.465
Borhade, Namdev ; Pathan, Asif Rahimkhan ; Halder, Somnath ; Karwa, Manoj ; Dhiman, Mini ; Pamidiboina, Venu ; Gund, Machhindra ; Deshattiwar, Jagannath Janardhan ; Mali, Sunil Vasantrao ; Deshmukh, Nitin Janardanrao ; Senthilkumar, Subrayan Palanisamy ; Gaikwad, Parikshit ; Tipparam, Santhosh Goud ; Mudgal, Jayesh ; Dutta, Milan Chandra ; Burhan, Aslam Usmangani ; Thakre, Gajanan ; Sharma, Ankur ; Deshpande, Shubhada ; Desai, Dattatraya Chandrakant ; Dubash, Nauzer Pervez ; Jain, Arun Kumar ; Sharma, Somesh ; Nemmani, Kumar Venkata Subrahmanya ; Satyam, Apparao. / NO-NSAIDs. Part 3 : Nitric oxide-releasing prodrugs of non-steroidal anti-inflammatory drugs. In: Chemical and Pharmaceutical Bulletin. 2012 ; Vol. 60, No. 4. pp. 465-481.
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author = "Namdev Borhade and Pathan, {Asif Rahimkhan} and Somnath Halder and Manoj Karwa and Mini Dhiman and Venu Pamidiboina and Machhindra Gund and Deshattiwar, {Jagannath Janardhan} and Mali, {Sunil Vasantrao} and Deshmukh, {Nitin Janardanrao} and Senthilkumar, {Subrayan Palanisamy} and Parikshit Gaikwad and Tipparam, {Santhosh Goud} and Jayesh Mudgal and Dutta, {Milan Chandra} and Burhan, {Aslam Usmangani} and Gajanan Thakre and Ankur Sharma and Shubhada Deshpande and Desai, {Dattatraya Chandrakant} and Dubash, {Nauzer Pervez} and Jain, {Arun Kumar} and Somesh Sharma and Nemmani, {Kumar Venkata Subrahmanya} and Apparao Satyam",
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Borhade, N, Pathan, AR, Halder, S, Karwa, M, Dhiman, M, Pamidiboina, V, Gund, M, Deshattiwar, JJ, Mali, SV, Deshmukh, NJ, Senthilkumar, SP, Gaikwad, P, Tipparam, SG, Mudgal, J, Dutta, MC, Burhan, AU, Thakre, G, Sharma, A, Deshpande, S, Desai, DC, Dubash, NP, Jain, AK, Sharma, S, Nemmani, KVS & Satyam, A 2012, 'NO-NSAIDs. Part 3: Nitric oxide-releasing prodrugs of non-steroidal anti-inflammatory drugs', Chemical and Pharmaceutical Bulletin, vol. 60, no. 4, pp. 465-481. https://doi.org/10.1248/cpb.60.465

NO-NSAIDs. Part 3 : Nitric oxide-releasing prodrugs of non-steroidal anti-inflammatory drugs. / Borhade, Namdev; Pathan, Asif Rahimkhan; Halder, Somnath; Karwa, Manoj; Dhiman, Mini; Pamidiboina, Venu; Gund, Machhindra; Deshattiwar, Jagannath Janardhan; Mali, Sunil Vasantrao; Deshmukh, Nitin Janardanrao; Senthilkumar, Subrayan Palanisamy; Gaikwad, Parikshit; Tipparam, Santhosh Goud; Mudgal, Jayesh; Dutta, Milan Chandra; Burhan, Aslam Usmangani; Thakre, Gajanan; Sharma, Ankur; Deshpande, Shubhada; Desai, Dattatraya Chandrakant; Dubash, Nauzer Pervez; Jain, Arun Kumar; Sharma, Somesh; Nemmani, Kumar Venkata Subrahmanya; Satyam, Apparao.

In: Chemical and Pharmaceutical Bulletin, Vol. 60, No. 4, 01.04.2012, p. 465-481.

Research output: Contribution to journalArticle

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.

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