The pharmacologic effects of 5-[3,5-bis(1,1-dimethylethyl)-4- hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione, choline salt (CI-986), a novel inhibitor of arachidonic acid metabolism in models of inflammation, analgesia and gastric irritation.
CI-986 is a potent inhibitor of 5-lipoxygenase and cyclooxygenase pathway product biosynthesis from rat basophilic leukemia (RBL) cells. Because metabolites from these pathways have proinflammatory properties, CI-986 was evaluated in several acute and chronic models of inflammation and hyperalgesia. The compound inhibited swelling in the carrageenan footpad edema, Mycobacterium foot-pad edema and adjuvant arthritis models of inflammation with ID40 values of 1.0, 7.7., and 7.2 mg/kg, respectively. It was roughly equivalent in potency to the standard selective cyclooxygenase inhibitor, naproxen (ID40 = 0.7, 6.3, and 3.8 mg/kg, respectively). CI-986 was also evaluated in the acetic acid induced writhing hyperalgesia assay (ID50 = 0.23 mg/kg) and was approximately equipotent with indomethacin (ID50 = 0.87 mg/kg). Although the effects of CI-986 were similar to those of standard nonsteroidal antiinflammatory drugs (NSAIDs) in the inflammation models, its gastrointestinal profile was unique. CI-986 caused no gastrointestinal irritation at doses up to 200 mg/kg in acute and chronic studies. In contrast, standard NSAIDs caused ulcers at doses of 3.7-37 mg/kg after a single dose. Moreover, CI-986 inhibited the release of LTC4 and PGE2 by gastric mucosa and reduced mucosal and vascular damage induced by oral administration of absolute ethanol to rats. These results indicate that CI-986 is a potent nonulcerogenic antiinflammatory agent with novel pharmacologic properties.
Schrier
D J
DJ
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Baragi
V M
VM
Connor
D T
DT
Dyer
R D
RD
Jordan
J H
JH
Imre
K M
KM
Lesch
M E
ME
Mullican
M D
MD
Okonkwo
G C
GC
Conroy
M C
MC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D016718:Arachidonic Acid / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000188:drug therapy; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D015237:Dinoprost / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004195:Disease Models, Animal; D000431:Ethanol; D005260:Female; D005756:Gastritis / Q000139:chemically induced / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D013830:Thiadiazoles / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D013830:Thiadiazoles; C080863:CI 986; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000431:Ethanol; D015237:Dinoprost