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Pharmacological properties of MDL 19,301: A novel, nonsteroidal, anti‐inflammatory agent
Author(s) -
Doherty Niall S.,
Beaver Thomas H.,
Westrich Gerald L.,
Miller Francis P.,
Roebel Lawrence E.
Publication year - 1989
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430160105
Subject(s) - pharmacology , chemistry , arachidonic acid , antipyretic , metabolite , oral administration , carrageenan , in vivo , edema , ed50 , anti inflammatory , medicine , biochemistry , analgesic , in vitro , enzyme , biology , microbiology and biotechnology
Oral administration of MDL 19,301 (N‐(1,3‐dithiolan‐2‐ylidene)‐4‐hexyl‐benzenamine) inhibited rat paw edema induced by carrageenan (ED30 4.8 mg/kg) or an Arthus reaction (ED30 8.2 mg/kg p.o.). The oral dose which induced gastric ulceration in 50% of fasted rats (UD50) was greater than 1,000 mg/kg, demonstrating a more favorable therapeutic ratio than conventional nonsteroidal anti‐inflammatory agents. Its major metabolite ((MDL16,861, 4[1,3‐dithiolan‐2‐yliden)amino]‐benzeneacetic acid) was also a potent inhibitor of carrageenan paw edema (ED50 5.5 mg/kg p.o.), although it was more ulcerogenic (UD50 52 mg/kg p.o.). The anti‐inflammatory activity of MDL 19,301, but not that of MDL 16,861, was attenuated by co‐administration of an inhibitor of drug metabolism (SK&F525A 30 mg/kg i.p.). This suggests that MDL 19,301 is a prodrug of MDL 16,861 and this phenomenon would explain its lack of ulcerogenicity. Additional anti‐inflammatory properties of MDL 19,301 included inhibition of carrageenan pleurisy, adjuvant arthritis, and acetic‐acid‐induced writhing. Other pharmacological data indicate that MDL 19,301 administration results in inhibition of prostaglandin synthesis; inhibition of arachidonic‐acid‐induced, but not prostaglandin‐E 2 ‐induced, diarrhea in mice; and inhibition of ex vivo arachidonic‐acid‐induced, but not adenosine‐diphosphate‐induced, rat platelet aggregation. MDL 19,301 and MDL 16,861 were unexpectedly weak antipyretic agents in rats. In summary, MDL 19,301 is an anti‐inflammatory, analgesic prodrug which, unlike conventional agents, is devoid of ulcerogenic activity at therapeutic doses.