title: Gastric-sparing nitric oxide-releasable 'true' prodrugs of aspirin and naproxen.
abstract: Nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) are gaining attention as potentially gastric-sparing NSAIDs. Herein, we report a novel class of '1-(nitrooxy)ethyl ester' group-containing NSAIDS as efficient NO releasing 'true' prodrugs of aspirin and naproxen. While an aspirin prodrug exhibited comparable oral bioavailability and antiplatelet activity (i.e., TXB2 inhibition) to those of aspirin, a naproxen prodrug exhibited better bioavailability than naproxen. These promising NO-NSAIDs protected experimental rats from gastric damage. We therefore believe that these promising NO-NSAIDs could represent a new class of potentially 'Safe NSAIDs' for the treatment of arthritic pain, inflammation and cardiovascular disorders in the case of NO-aspirin.
authors.affiliation: Medicinal Chemistry Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India.
authors.forename: Machhindra
authors.initials: M
authors.lastname: Gund
authors.affiliation: Pharmacology Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India.
authors.forename: Parikshit
authors.initials: P
authors.lastname: Gaikwad
authors.affiliation: Medicinal Chemistry Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India.
authors.forename: Namdev
authors.initials: N
authors.lastname: Borhade
authors.affiliation: Pharmacology Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India.
authors.forename: Aslam
authors.initials: A
authors.lastname: Burhan
authors.affiliation: Analytical Chemistry-Medicinal Chemistry Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India.
authors.forename: Dattatraya C
authors.initials: DC
authors.lastname: Desai
authors.affiliation: Pharmacology Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India.
authors.forename: Ankur
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Analytical Chemistry-Medicinal Chemistry Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India.
authors.forename: Mini
authors.initials: M
authors.lastname: Dhiman
authors.affiliation: Pharmacology Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India.
authors.forename: Mohan
authors.initials: M
authors.lastname: Patil
authors.affiliation: Medicinal Chemistry Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India.
authors.forename: Javed
authors.initials: J
authors.lastname: Sheikh
authors.affiliation: Medicinal Chemistry Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India.
authors.forename: Gajanan
authors.initials: G
authors.lastname: Thakre
authors.affiliation: Medicinal Chemistry Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India.
authors.forename: Santhosh G
authors.initials: SG
authors.lastname: Tipparam
authors.affiliation: Pharmacology Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India.
authors.forename: Somesh
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Pharmacology Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India.
authors.forename: Kumar V S
authors.initials: KVS
authors.lastname: Nemmani
authors.affiliation: Medicinal Chemistry Division, Piramal Life Sciences, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon East, Mumbai 400063, India. Electronic address: apparaosvgk@hotmail.com.
authors.forename: Apparao
authors.initials: A
authors.lastname: Satyam
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D019540:Area Under Curve; D001241:Aspirin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004355:Drug Stability; D005753:Gastric Mucosa / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D009288:Naproxen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D009566:Nitrates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D009569:Nitric Oxide / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D012372:ROC Curve; D051381:Rats; D017207:Rats, Sprague-Dawley; D013929:Thromboxane B2 / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C488176:N-acetyl-S-(alpha-methyl-4-(2-methylpropyl)benzeneacetyl)cysteine 4-(nitrooxy)butyl ester; D009566:Nitrates; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; C111751:naproxen-n-butyl nitrate; D009569:Nitric Oxide; D013929:Thromboxane B2; D009288:Naproxen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D001241:Aspirin
keywords: Gastric-sparing NSAIDs; NO-NSAIDs; NO-aspirin; NO-naproxen; Nitric oxide donors