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 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 MeSO2 COX-2 pharmacophore exhibited superior AI activity compared to analogs having a H2NSO2 substituent. Compounds having a MeSO2 COX-2 pharmacophore in conjunction with a N-(4-nitrooxybutyl)piperidyl (ED50=132.4 mg/kg po), or a N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridyl (ED50=118.4 mg/kg po), moiety exhibited an AI potency profile that is similar to aspirin (ED50=128.7 mg/kg po) but lower than ibuprofen (ED50=67.4 mg/kg po).
Chowdhury
Morshed A
MA
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta, Canada T6G 2N8.
Abdellatif
Khaled R A
KR
Dong
Ying
Y
Yu
Gang
G
Huang
Zhangjian
Z
Rahman
Moshfiqur
M
Das
Dipankar
D
Velázquez
Carlos A
CA
Suresh
Mavanur R
MR
Knaus
Edward E
EE
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D000068579:Celecoxib; D018360:Crystallography, X-Ray; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007052:Ibuprofen / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009569:Nitric Oxide / Q000737:chemistry*; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry*; D051381:Rats; D012756:Sheep; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*
D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D020030:Nitric Oxide Donors; D010880:Piperidines; D011355:Prodrugs; D011720:Pyrazoles; D013449:Sulfonamides; D009569:Nitric Oxide; D000068579:Celecoxib; D001241:Aspirin; D007052:Ibuprofen