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.