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Celecoxib analogs possessing a N-(4-nitrooxybutyl)piperidin-4-yl or N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridin-4-yl nitric oxide donor moiety: Synthesis, biological evaluation and nitric oxide release studies
A new group of hybrid nitric oxide (NO) releasing anti-inflammatory (AI) coxib prodrugs (NO-coxibs) wherein the para-tolyl moiety present in celecoxib was replaced by a N-(4-nitrooxybutyl)piperidyl 15a– b, or N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridyl 17a– b, NO-donor moiety was synthesized. All...
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Published in: | Bioorganic & medicinal chemistry letters 2010-02, Vol.20 (4), p.1324-1329 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | A new group of hybrid nitric oxide (NO) releasing anti-inflammatory (AI) coxib prodrugs (NO-coxibs) wherein the
para-tolyl moiety present in celecoxib was replaced by a
N-(4-nitrooxybutyl)piperidyl
15a–
b, or
N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridyl
17a–
b, NO-donor moiety was synthesized. All compounds released a low amount of NO upon incubation with phosphate buffered saline (PBS) at pH 7.4 (2.4–5.8% range). In comparison, the percentage NO released was higher (3.1–8.4% range) when these nitrate prodrugs were incubated in the presence of
l-cysteine. In vitro COX-1/COX-2 isozyme inhibition studies showed this group of compounds are moderately more potent, and hence selective, inhibitors of the COX-2 relative to the COX-1 enzyme. AI structure–activity relationship data acquired showed that compounds having a MeSO
2 COX-2 pharmacophore exhibited superior AI activity compared to analogs having a H
2NSO
2 substituent. Compounds having a MeSO
2 COX-2 pharmacophore in conjunction with a
N-(4-nitrooxybutyl)piperidyl (ED
50
=
132.4
mg/kg po), or a
N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridyl (ED
50
=
118.4
mg/kg po), moiety exhibited an AI potency profile that is similar to aspirin (ED
50
=
128.7
mg/kg po) but lower than ibuprofen (ED
50
=
67.4
mg/kg po). |
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ISSN: | 0960-894X 1464-3405 |
DOI: | 10.1016/j.bmcl.2010.01.014 |