A novel class of 1-(4-methanesulfonylphenyl and 4-aminosulfonylphenyl)-5-[4-(1-difluoromethyl-1,2-dihydropyrid-2-one)]-3-trifluoromethyl-1H-pyrazole hybrid cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory anti-inflammatory agents was designed. Replacement of the tolyl ring present in celecoxib by the N-difluoromethyl-1,2-dihydropyrid-2-one moiety provided compounds showing dual selective COX-2/5-LOX inhibitory activities. 1-(4-Aminosulfonylphenyl)-5-[4-(1-difluoromethyl-1,2-dihydropyrid-2-one)]-3-trifluoromethyl-1H-pyrazole exhibited good anti-inflammatory (AI) activity (ED(50) = 27.7 mg/kg po) that compares favorably with the reference drugs celecoxib (ED(50) = 10.8 mg/kg po) and ibuprofen (ED(50) = 67.4 mg/kg po). The N-difluoromethyl-1,2-dihydropyridin-2-one moiety provides a novel 5-LOX pharmacophore for the design of cyclic hydroxamic mimetics for exploitation in the development of COX-2/5-LOX inhibitory AI drugs.
Chronic inflammation is an underlying etiological factor in carcinogenesis; nonsteroidal anti-inflammatory drugs (NSAIDs) and their chemically modified NO-releasing prodrugs (NO-NSAIDs) are promising chemopreventive agents. The aim of this study was to conduct a head-to-head comparison between two NO-ASAs possessing different NO donor groups, an organic nitrate [3-nitrooxyphenyl acetylsalicylate (NO-ASA; NCX-4016)] and an N-diazeniumdiolate [NONO-ASA, O 2 -(acetylsalicyloxymethyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (NONO-ASA; CVM-01)], as antiulcerogenic, analgesic, anti-inflammatory, and antipyretic agents. All drugs were administered orally at equimolar doses. For antiulcerogenic study, 6 h after administration, the number and size of hemorrhagic lesions in stomachs from euthanized animals were counted. Tissue samples were frozen for prostaglandin E 2 (PGE 2 ), superoxide dismutase (SOD), and malondialdehyde determination. For anti-inflammatory study, 1 h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 6 h. For antipyretic study, 1 h after dosing, fever was induced by intraperitoneal LPS, and body core temperatures measured for 5 h. For analgesic study, time-dependent analgesic effect of prodrugs was evaluated by carrageenan-induced hyperalgesia. Drugs were administered 30 min after carrageenan. NO-ASA and NONO-ASA were equipotent as analgesic and anti-inflammatory agents but were better than aspirin. Despite a drastic reduction of PGE 2 in stomach tissue, both prodrugs were devoid of gastric side effects. Lipid peroxidation induced by aspirin was higher than that observed by prodrugs. SOD activity induced by both prodrugs was similar, but approximately 2-fold higher than that induced by aspirin. CVM-01 is as effective as NCX-4016 in anti-inflammatory, analgesic, and antipyretic assays in vivo, and it showed an equivalent safety profile in the stomach. These results underscore the use of N-diazeniumdiolate moieties in drug design.
The carboxylic acid group of the anti-inflammatory (AI) drugs indo-methacin, (S)-naproxen and ibuprofen was covalently linked via a two-carbon ethyl spacer to a sulfohydroxamic acid moiety (CH(2)CH(2)SO(2)NHOH) to furnish a group of hybrid ester prodrugs that release nitric oxide (NO) and nitroxyl (HNO). Biological data acquired for this hitherto unknown class of ethanesulfohydroxamic acid ester prodrugs showed (i) all compounds exhibited superior NO, but similar HNO, release properties relative to arylsulfohydroxamic acids, (ii) the (S)-naproxen and ibuprofen prodrug esters are more potent AI agents than their parent NSAID, (iii) the indomethacin prodrug ester, in contrast to indomethacin which is highly ulcerogenic, showed no visible stomach lesions [ulcer index (UI) = 0 for a 80 μmol/kg oral dose] while retaining potent AI activity, and iv) that the indomethacin prodrug ester, unlike indomethacin which is an ulcerogenic selective COX-1 inhibitor, is a selective COX-2 inhibitor (COX-2 selectivity index = 184) devoid of ulcerogenicity that is attributed to its high COX-2 SI and/or ability to release cytoprotective NO.
In a new group of 3-methyl-2-phenyl-1-substituted-indole derivatives (10a-f), the indomethacin analogs were prepared via the Fisher indole synthesis reaction of propiophenone with appropriately substituted phenylhydrazine hydrochloride. This is followed by the insertion of the appropriate benzyl or benzoyl fragment. All the synthesized compounds were evaluated for their anti-inflammatory (in vitro and in vivo) and analgesic activities. The methanesulphonyl derivatives 10d, e and f showed the highest anti-inflammatory (in vitro and in vivo) and analgesic activities. In addition, molecular docking studies were performed on compounds 10a-f and the results were in agreement with that obtained from the in vitro COX inhibition assays. The significant anti-inflammatory and analgesic activities exhibited by 10d and 10e warrant continued preclinical development as potential anti-inflammatory and analgesic agents.
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