Premium
Development of a substituted phenyldithiolethione as a novel cyclooxygenase inhibitor with minimal gastro‐irritancy
Author(s) -
Jarrott Bevyn,
Zanatta Shan,
Williams Spencer John
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.lb369
Subject(s) - diclofenac , chemistry , cyclooxygenase , pharmacology , antioxidant , hydrogen sulfide , analgesic , anti inflammatory , inflammation , toxicity , stereochemistry , biochemistry , enzyme , medicine , organic chemistry , immunology , sulfur
Hydrogen sulfide has been proposed as an endogenous molecule that inhibits early stages of inflammation. Dithiolethiones can be metabolised to hydrogen sulfide and when coupled to diclofenac produce a compound that is an anti‐inflammatory/analgesic agent without the gastrointestinal toxicity of diclofenac (Wallace 2007). Previous research has shown that compounds containing an antioxidant moiety, 3,5‐di‐tert‐butyl‐4‐hydroxy‐phenyl were cyclooxygenase (COX) inhibitors (Ruiz et al 2003) so we hypothesised that the attachment of a dithiolethione ring onto this antioxidant may give a compound that inhibited COX and also released hydrogen sulfide. We therefore synthesised and tested 5‐(3,5‐di‐tert‐butyl‐4‐hydroxyphenyl)‐3H‐1,2‐dithiole‐3‐thione and this inhibited purified COX‐1 with an IC 50 of 2 µM and COX‐2 with an IC 50 of 0.25 µM. After oral administration at a dose of 10 µmol/kg, this compound was anti‐inflammatory in a rat model of inflammation and pain (Complete Freund's adjuvant hind paw model) and had reduced gastrointestinal toxicity in rats (n = 9) when compared to an equivalent dose of diclofenac. Also, in view of the lipid solubility of this compound, it may be centrally acting and neuroprotective in diseases with central inflammatory pathologies.