Synthesis and anti-inflammatory activity of a series of N-substituted naproxen glycolamides: nitric oxide-donor naproxen prodrugs.
A series of glycolamide naproxen prodrugs containing a nitrate group as a nitric oxide (NO) donor moiety has been synthesized. These compounds were evaluated for their anti-inflammatory activity, naproxen release, and gastric tolerance. Compounds 4a, 4b, 5a, 5b, 7b, and 7c exhibited anti-inflammatory activity equivalent to that of the parent NSAID, naproxen-Na, in the rat carrageenan paw edema model. At equimolar doses relative to naproxen-Na, the NO-donor glycolamide derivatives 4a, 4b, 5a, 5b, 7b, and 7c were gastro-sparing in the rat. Naproxen formation from these NO-donor glycolamides varied among the structures examined, with the N-substituent on the amide group having a particular influence, and demonstrated their prodrug nature. Compound 7b was selected for exemplary demonstration that the glycolamide nitrates can be bioactivated to release NO. These data open the possibility that naproxen glycolamide nitrates may represent a safer alternative to naproxen as anti-inflammatory medicines.
Ranatunge
Ramani R
RR
NitroMed, Inc., 125 Spring St., Lexington, MA 02421, USA. ramani@nitromed.com
Augustyniak
Michael E
ME
Dhawan
Vijay
V
Ellis
James L
JL
Garvey
David S
DS
Janero
David R
DR
Letts
L Gordon
LG
Richardson
Stewart K
SK
Shumway
Mathew J
MJ
Trocha
A Mark
AM
Young
Delano V
DV
Zemtseva
Irina S
IS
D000577:Amides / Q000737:chemistry; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005756:Gastritis / Q000139:chemically induced; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D009288:Naproxen / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs; D051381:Rats; D017207:Rats, Sprague-Dawley
D000577:Amides; D000893:Anti-Inflammatory Agents; D020030:Nitric Oxide Donors; D011355:Prodrugs; D009288:Naproxen