CI-986

CI-986 (5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3, 4-thiadizole-2(3H)-thione, choline salt) was evaluated for its effect on arachidonic acid metabolism by human neutrophils in response to different stimuli. Leukotriene B4 (LTB4) release in response to calcium ionophore A23187 was 15 to 35 fold greater than the responses to N-formyl-methionyl-leucyl-phenylalanine (FMLP) or serum-opsonized zymosan (SOZ), respectively, while the thromboxane B2 (TXB2) release response was similar for the three stimuli tested. CI-986 inhibited the release of LTB4 and TXB2 in response to A23187 with IC50s of 63.4 and 1.6 microM, respectively. In comparison, the compound inhibited SOZ-stimulated LTB4 release with an IC50 of 11.2 microM, while having no effect on TXB2 at concentrations up to 100 microM. Conversely, CI-986 inhibited FMLP-stimulated LTB4 release by 42% at 100 microM, while inhibiting TXB2 release with an IC50 of 0.13 microM. These results demonstrate a stimulus-dependent inhibitory effect of CI-986 on human neutrophil eicosanoid metabolism.

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.