Structure-based design, synthesis, and biological evaluation of indomethacin derivatives as cyclooxygenase-2 inhibiting nitric oxide donors.
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.
Wey
Shiow-Jyi
SJ
NitroMed, Inc., 125 Spring Street, Lexington, Massachusetts 02421, USA. swey@comcast.net
Augustyniak
Michael E
ME
Cochran
Edward D
ED
Ellis
James L
JL
Fang
Xinqin
X
Garvey
David S
DS
Janero
David R
DR
Letts
L Gordon
LG
Martino
Allison M
AM
Melim
Terry L
TL
Murty
Madhavi G
MG
Richardson
Steward K
SK
Schroeder
Joseph D
JD
Selig
William M
WM
Trocha
A Mark
AM
Wexler
Roseanne S
RS
Young
Delano V
DV
Zemtseva
Irina S
IS
Zifcak
Brian M
BM
D000818:Animals; D001241:Aspirin / Q000009:adverse effects; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004357:Drug Synergism; D005260:Female; D005753:Gastric Mucosa / Q000473:pathology; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology; D007213:Indomethacin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D020030:Nitric Oxide Donors / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D006877:Hydroxamic Acids; D020030:Nitric Oxide Donors; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib; D001241:Aspirin; D007213:Indomethacin