A novel group of hybrid
nitric oxide-releasing nonsteroidal antiinflammatory drugs ((*)NO-
NSAIDs) possessing a 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11, 13, 15) or 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (12, 14, 16) moiety attached via a one-
carbon methylene spacer to the
carboxylic acid group of the traditional
NSAIDs aspirin,
ibuprofen, and
indomethacin were synthesized. Although none of these
ester prodrugs (11-16) exhibited in vitro
cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2
isozymes (IC(50) > 100 microM), all of the compounds (11-16) significantly decreased
carrageenan-induced rat paw
edema. In this regard, the
ester prodrugs 11-16 showed equipotent antiinflammatory activities in vivo to that of the parent drugs
aspirin,
ibuprofen, and
indomethacin. All of the compounds released
nitric oxide upon incubation with either
phosphate buffer solution at pH 7.4 (14-16% range) or porcine liver
esterase (16-19% range), but the percentage of (*)NO released was up to sixfold higher (93%) when these
ester prodrugs were incubated with guinea pig serum. These incubation studies suggest that both (*)NO and the parent
NSAID would be released upon in vivo cleavage by nonspecific serum
esterases. The simultaneous release of
aspirin and
nitric oxide from the (*)
NO-aspirin prodrugs constitutes a potentially beneficial property for the prophylactic prevention of
thrombus formation and adverse cardiovascular events such as
stroke and
myocardial infarction. The data acquired in an in vivo
ulcer index (UI) assay showed that for this group of
ester prodrugs, particularly the (*)NO-aspirins (11, 12) and (*)NO-ibuprofens (13, 14), no lesions were observed (UI = 0) when compared to the parent drugs
aspirin (UI = 57, 250 mg/kg po dose),
ibuprofen (UI = 45, 250 mg/kg po dose), or
indomethacin (UI = 34, 30 mg/kg po dose) at equivalent doses. Accordingly, these hybrid (*)NO-
NSAID prodrugs possessing a
diazen-1-ium-1,2-diolate moiety, represent a new approach for the rational design of antiinflammatory drugs with reduced gastric ulcerogenicity.