Nitrosothiol esters of diclofenac: synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs.
Despite its widespread use, diclofenac has gastrointestinal liabilities common to nonsteroidal antiinflammatory drugs (NSAIDs) that might be reduced by concomitant administration of a gastrointestinal cytoprotectant such as nitric oxide (NO). A series of novel diclofenac esters containing a nitrosothiol (-S-NO) moiety as a NO donor functionality has been synthesized and evaluated in vivo for bioavailability, pharmacological activity, and gastric irritation. All S-NO-diclofenac derivatives acted as orally bioavailable prodrugs, producing significant levels of diclofenac in plasma within 15 min after oral administration to mice. At equimolar oral doses, S-NO-diclofenac derivatives (20a-21b) displayed rat antiinflammatory and analgesic activities comparable to those of diclofenac in the carrageenan-induced paw edema test and the mouse phenylbenzoquinone-induced writhing test, respectively. All tested S-NO-diclofenac derivatives (20a-21b) were gastric-sparing in that they elicited markedly fewer stomach lesions as compared to the stomach lesions caused by a high equimolar dose of diclofenac in the rat. Nitrosothiol esters of diclofenac comprise a novel class of NO-donating compounds having therapeutic potential as nonsteroidal antiinflammatory agents with an enhanced gastric safety profile.
Bandarage
U K
UK
NitroMed, Inc., 12 Oak Park Drive, Bedford, Massachusetts 01730, USA. ubandarage@nitromed.com
Chen
L
L
Fang
X
X
Garvey
D S
DS
Glavin
A
A
Janero
D R
DR
Letts
L G
LG
Mercer
G J
GJ
Saha
J K
JK
Schroeder
J D
JD
Shumway
M J
MJ
Tam
S W
SW
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D004008:Diclofenac / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D009603:Nitroso Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000473:pathology; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D009603:Nitroso Compounds; D011355:Prodrugs; D004008:Diclofenac