NMI-1182, a gastro-protective cyclo-oxygenase-inhibiting nitric oxide donor.
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammation and to provide pain relief but suffer from a major liability concerning their propensity to cause gastric damage. As nitric oxide (NO) is known to be gastro-protective we have synthesized a NO-donating prodrug of naproxen named NMI-1182. We evaluated two cyclo-oxygenase (COX)-inhibiting nitric oxide donors (CINODs), NMI-1182 and AZD3582, for their ability to be gastro-protective compared to naproxen and for their anti-inflammatory activity. NMI-1182 and AZD3582 were found to produce similar inhibition of COX activity to that produced by naproxen. Both NMI-1182 and AZD3582 produced significantly less gastric lesions after oral administration than naproxen. All three compounds effectively inhibited paw swelling in the rat carrageenan paw edema model. In the carrageenan air pouch model all three compounds significantly reduced PGE2 levels in the pouch exudate but only NMI-1182 and naproxen inhibited leukocyte influx. These data demonstrate that NMI-1182 has comparable anti-inflammatory activity to naproxen but with a much reduced likelihood to cause gastric damage.
Ellis
James L
JL
NitroMed Inc., 125 Spring Street, Lexington, MA 02421-0781, USA. jellis@nitromed.com
Augustyniak
Michael E
ME
Cochran
Edward D
ED
Earl
Richard A
RA
Garvey
David S
DS
Gordon
Laura J
LJ
Janero
David R
DR
Khanapure
Subhash P
SP
Letts
L Gordon
LG
Melim
Terry L
TL
Murty
Madhavi G
MG
Schwalb
David J
DJ
Shumway
Matthew J
MJ
Selig
William M
WM
Trocha
A Mark
AM
Young
Delano V
DV
Zemtseva
Irina S
IS
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D001012:Aorta, Abdominal / Q000187:drug effects / Q000502:physiology; D002351:Carrageenan; D051545:Cyclooxygenase 1 / Q000097:blood; D051546:Cyclooxygenase 2 / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D015394:Molecular Structure; D009281:Naphthalenes / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D009288:Naproxen / Q000097:blood / Q000737:chemistry / Q000494:pharmacology / Q000031:analogs & derivatives; D020556:Neutrophil Infiltration / Q000187:drug effects; D020030:Nitric Oxide Donors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; C505683:NMI-1182; D009281:Naphthalenes; D020030:Nitric Oxide Donors; D020011:Protective Agents; C519797:des-NO-NMI-1182; C111751:naproxen-n-butyl nitrate; D009288:Naproxen; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone