Structure-based design, synthesis, and biological evaluation of indomethacin derivatives as cyclooxygenase-2 inhibiting nitric oxide donors.

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Wey SJ, Augustyniak ME, Cochran ED, Ellis JL, Fang X, Garvey DS, Janero DR, Letts LG, Martino AM, Melim TL, Murty MG, Richardson SK, Schroeder JD, Selig WM, Trocha AM, Wexler RS, Young DV, Zemtseva IS, Zifcak BM

Structure-based design, synthesis, and biological evaluation of indomethacin derivatives as cyclooxygenase-2 inhibiting nitric oxide donors.

J Med Chem. 2007 Dec 13;50(25):6367-82. Epub 2007 Nov 10.

PubMed ID

17994684 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Celecoxib	Prostaglandin G/H synthase 2	IC 50 (nM)	1200	N/A	N/A	Details
Indomethacin	Prostaglandin G/H synthase 1	IC 50 (nM)	500	N/A	N/A	Details
Indomethacin	Prostaglandin G/H synthase 2	IC 50 (nM)	700	N/A	N/A	Details