Celecoxib prodrugs possessing a diazen-1-ium-1,2-diolate nitric oxide donor moiety: synthesis, biological evaluation and nitric oxide release studies.
A new class of anti-inflammatory (AI) cupferron prodrugs was synthesized wherein a diazen-1-ium-1,2-diolato ammonium salt, and its O(2)-methyl and O(2)-acetoxyethyl derivatives, nitric oxide (NO) donor moieties were attached directly to an aryl carbon on a celecoxib template. The percentage of NO released from the O(2)-methyl and O(2)-acetoxyethyl compounds was higher (18.0-37.8% of the theoretical maximal release of one molecule of NO/molecule of the parent compound) upon incubation in the presence of rat serum, relative to incubation with phosphate buffer saline (PBS) at pH 7.4 (3.8-11.6% range). All compounds exhibited weak inhibition of the COX-1 isozyme (IC(50)=5.8-17.0 microM range) in conjunction with weak or modest inhibition of the COX-2 isozyme (IC(50)=1.6-14.4 microM range). The most potent AI agent 5-[4-(O(2)-ammonium diazen-1-ium-1,2-diolato)phenyl]-1-(4-sulfamoylphenyl)-3-trifluoromethyl-1H-pyrazole exhibited a potency that was about fourfold and twofold greater than that observed for the respective reference drugs aspirin and ibuprofen. These studies indicate that use of a cupferron template constitutes a plausible drug design approach targeted toward the development of AI drugs that do not cause gastric irritation, or elevate blood pressure and induce platelet aggregation that have been associated with the use of some selective COX-2 inhibitors.
Abdellatif
Khaled R A
KR
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Chowdhury
Morshed A
MA
Velázquez
Carlos A
CA
Huang
Zhangjian
Z
Dong
Ying
Y
Das
Dipankar
D
Yu
Gang
G
Suresh
Mavanur R
MR
Knaus
Edward E
EE
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000068579:Celecoxib; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D006834:Hydrazines / Q000737:chemistry*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000737:chemistry*; D009602:Nitrosamines / Q000138:chemical synthesis / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
C507406:1-isopropyldiazen-1-ium-1,2-diolate; D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D006834:Hydrazines; D020030:Nitric Oxide Donors; D009602:Nitrosamines; D011355:Prodrugs; D011720:Pyrazoles; D013449:Sulfonamides; D009569:Nitric Oxide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000068579:Celecoxib; C031808:cupferron