Enhancing the pharmacodynamic profile of a class of selective COX-2 inhibiting nitric oxide donors

Abstract

We report herein the development, synthesis, physicochemical and pharmacological characterization of a novel class of pharmacodynamic hybrids that selectively inhibit cyclooxygenase-2 (COX-2) isoform and present suitable nitric oxide releasing properties. The replacement of the ester moiety with the amide group gave access to in vivo more stable and active derivatives that highlighted outstanding pharmacological properties. In particular, the glycine derivative proved to be extremely active in suppressing hyperalgesia and edema.

Keywords: (t)NSAIDs; 1,5-Diarylpyrroles; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; 1-hydroxybenzotriazole; 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; AA; Boc; CBz; CINODs; COX-2; CV; Coxibs; Cyclooxygenases; DMAP; DMEM; Dulbecco’s modified eagle’s medium; E(max); EDCI; FBS; GI; HOBt; HWB; LPS; NO; NO releasing moiety (nitroxy)butanol; NOBA; NSAIDs; Nitric oxide; OA; ODQ; PBS; PGE(2); Pharmacodynamic hybrids; PyBOP; RA; RIA; SAR; SGF; TX; arachidonic acid; benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate; cNOS; carboxybenzyl; cardiovascular; constitutive nitric oxide synthases; coxibs; cyclooxygenase 2; cyclooxygenase-2 inhibitors; cyclooxygenase-inhibiting nitric oxide donor; dimethylaminopyridine; fetal bovine serum; gastrointestinal; human whole blood; intraperitoneal; intraplantar; ip; ipl; lipopolysaccharide; maximal vasorelaxing response; nitric oxide; nonsteroidal anti-inflammatory drug; osteoarthritis; phosphate buffer solution; prostaglandin E(2); radioimmunoassay; rheumatoid arthritis; simulated gastric fluid; structure relationship studies; tert-butyloxycarbonyl; thromboxane; traditional nonsteroidal anti-inflammatory drug.