Diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of 1-(4-methanesulfonylphenyl)-5-aryl-1H-pyrazol-3-carboxylic acids: synthesis, nitric oxide release studies and anti-inflammatory activities.
A new group of hybrid nitric oxide-releasing anti-inflammatory drugs (NONO-coxibs) wherein an O(2)-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (11a-c) NO-donor moiety is attached directly to the carboxylic acid group of 1-(4-methanesulfonylphenyl)-5-aryl-1H-pyrazol-3-carboxylic acids were synthesized. The diazen-1-ium-1,2-diolate compounds 11a-c all released a low amount of NO upon incubation with phosphate buffer (PBS) at pH 7.4 (7.7-9.3% range). In comparison, the percentage of NO released was significantly higher (67.5-73.6% of the theoretical maximal release of two molecules of NO/molecule of the parent hybrid ester prodrug) when the diazen-1-ium-1,2-diolate ester prodrugs were incubated in the presence of rat serum. These incubation studies suggest that both NO and the anti-inflammatory 1-(4-methanesulfonylphenyl)-5-(4-H, 4-F or 4-Me-phenyl)-1H-pyrazol-3-carboxylic acid (9a-c) would be released from the parent NONO-coxib upon in vivo cleavage by non-specific serum esterases. The 1-(4-methanesulfonylphenyl)-5-(4-H, 4-F or 4-Me-phenyl)-1H-pyrazol-3-carboxylic acids (9a-c) exhibited AI activities (ID(50)=85.2-104.4 mg/kg po range) between that exhibited by the reference drugs aspirin (ID(50)=128.7 mg/kg po) and celecoxib (ID(50)=10.8 mg/kg po). Hybrid ester anti-inflammatory/NO-donor prodrugs (NONO-coxibs) offers a potential drug design concept targeted toward the development of anti-inflammatory drugs that are devoid of adverse ulcerogenic and/or cardiovascular effects.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta., Canada T6G 2N8.
Khaled R A
KR
Abdellatif
Morshed Alam
MA
Chowdhury
Ying
Y
Dong
Edward E
EE
Knaus
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D004952:Esters / Q000737:chemistry*; D006834:Hydrazines / Q000737:chemistry*; D007249:Inflammation / Q000188:drug therapy; D015394:Molecular Structure; D009569:Nitric Oxide / Q000737:chemistry*; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D004952:Esters; D006834:Hydrazines; D020030:Nitric Oxide Donors; D011355:Prodrugs; D011720:Pyrazoles; D009569:Nitric Oxide