Structure-Based Design, Synthesis, and Biological Evaluation of Indomethacin Derivatives as Cyclooxygenase-2 Inhibiting Nitric Oxide Donors

Abstract

Indomethacin, a nonselective cyclooxygenase (COX) inhibitor, was modified in three distinct regions in an attempt both to increase cyclooxygenase-2 (COX-2) selectivity and to enhance drug safety by covalent attachment of an organic nitrate moiety as a nitric oxide donor. A human whole-blood COX assay shows the modifications on the 3-acetic acid part of the indomethacin yielding an amide-nitrate derivative 32 and a sulfonamide-nitrate derivative 61 conferred COX-2 selectivity. Along with their respective des-nitrate analogs, for example, 31 and 62, the nitrates 32 and 61 were effective antiinflammatory agents in the rat air-pouch model. After oral dosing, though, only 32 increased nitrate and nitrite levels in rat plasma, indicating that its nitrate tether served as a nitric oxide donor in vivo. In a rat gastric injury model, examples 31 and 32 both show a 98% reduction in gastric lesion score compared to that of indomethacin. In addition, the nitrated derivative 32 inducing 85% fewer gastric lesions when coadministered with aspirin as compared to the combination of aspirin and valdecoxib.

Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), More Than Meets the Eye: A Critical Review

“…The first example is the nitrate-containing amide of indomethacin 16 (Figure 16), which is not a prodrug, because its stable amide linkage is not hydrolyzed for a timely release of the parent compound. This compound was shown to be a nitric oxide-releasing, mildly selective COX-2 inhibitor and an effective in vivo anti-inflammatory agent [65]. By contrast, its ester analogs 17 and 18 (Figure 16), are considered to be NO-releasing prodrugs of indomethacin, due to the observed fast hydrolysis of the ester linkages in these molecules [66,67].…”

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Progress in Small Molecule Drug Development

“…It should be noted that these novel CINODs exhibit decreased COX inhibitory potency relative to the lead selective COX-2 inhibitor cimicoxib (COX-2 IC 50 = 0.10 µM; COX-1 IC 50 = 1.9 µM). Recently, NitroMed Inc. reported a group of indomethacin derivatives as selective COX-2 inhibitors with NO-donating properties [33]. The indomethacin amide derivative possessing an organic nitrate NO-donor moiety ( 10 , Figure 3) exhibited effective in vitro COX-2 selectivity (COX-2 IC 50 = 1.2 µM; COX-1 IC 50 = 6.0 µM) and oral anti-inflammatory activity.…”

Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH2Sand their Prodrugs

“…Examples of this approach include nitro-nonsteroidals (e.g., nitroaspirin, SNO-diclofenac, nitrofenac), nitro-steroids, nitro-statins (e.g., nitro-pravastatin) and SNOcaptopril, and the alpha-receptor ligands nitroyohimbine and nitro-moxysylyte ( Fig NaN). The synthesis, characterization, preclinical, and clinical testing of the multiple compounds of this class have been covered by separate overviews (e.g., [412, [481][482][483][484][485][486][487]). …”