Novel (E)-2-(aryl)-3-(4-methanesulfonylphenyl)acrylic ester prodrugs possessing a diazen-1-ium-1,2-diolate moiety: design, synthesis, cyclooxygenase inhibition, and nitric oxide release studies.
A novel group of hybrid nitric oxide-releasing anti-inflammatory drugs (11) possessing a 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate, or 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate, nitric oxide (.NO) donor moiety attached via a one-carbon methylene spacer to the carboxylic acid group of (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acids were synthesized. These ester prodrugs (11) all exhibited in vitro inhibitory activity against the cyclooxygenase-2 (COX-2) isozyme (IC(50)=0.94-31.6 microM range). All compounds released .NO upon incubation with phosphate buffer (PBS) at pH 7.4 (3.2-11.3% range). In comparison, the percentage of .NO released was significantly higher (48.6-75.3% range) when these hybrid ester prodrugs were incubated in the presence of rat serum. These incubation studies suggest that both .NO and the parent anti-inflammatory (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acid would be released upon in vivo cleavage by non-specific serum esterases. O(2)-[(E)-2-(4-Acetylaminophenyl)-3-(4-methanesulfonylphenyl)acryloyloxymethyl]-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11f) is a moderately potent (IC(50)=0.94 microM) and selective (SI>104) COX-2 inhibitor that released 73% of the theoretical maximal release of two molecules of .NO/molecule of the parent hybrid ester prodrug upon incubation with rat serum. Hybrid ester .NO-donor prodrugs offer a potential drug design concept for the development of anti-inflammatory drugs that are devoid of adverse ulcerogenic and/or cardiovascular side effects.
Abdellatif
Khaled R A
KR
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, ALTA, Canada.
Dong
Ying
Y
Chen
Qiao-Hong
QH
Chowdhury
Morshed Alam
MA
Knaus
Edward E
EE
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007094:Imides / Q000737:chemistry; D009569:Nitric Oxide / Q000737:chemistry; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007094:Imides; D020030:Nitric Oxide Donors; D011355:Prodrugs; D013450:Sulfones; D009569:Nitric Oxide; D011451:Prostaglandin-Endoperoxide Synthases; C038867:diazene