Reduction of inflammation and pyrexia in the rat by oral administration of SDZ 224‐015, an inhibitor of the interleukin‐1β converting enzyme

Abstract

The aim of this study was to determine whether a synthetic inhibitor of the interleukin‐1β converting enzyme (ICE) displays oral activity in models of inflammation. To this end, the ICE inhibitor, SDZ 224‐015, was examined in rat paw oedema, pyrexia and nociception tests. SDZ 224‐015 (0.3–300 μg kg−1) potently reduced carrageenin‐induced paw oedema, with an oral ED50 of approximately 25 μg kg−1. This effect was independent of endogenous glucocorticoid, as shown by retention of activity upon adrenalectomy. Pyrexia induced by lipopolysaccharide (0.1 mg kg−1 s.c.) or by interleukin‐1β (100 ng i.v.) was also reduced, over a similar dose‐range to oedema (oral ED50S 11 μg kg−1 and 4 μg kg−1 respectively). SDZ 224‐015 (0.2–5 mg kg−1, p.o.) displayed analgesic activity in the Randall‐Selitto yeast‐inflamed paw pressure test, significant at a dose of 1 mg kg−1, p.o. 6 Thus, SDZ 224‐015 has potent oral activity in several acute models for inflammation, suggesting that ICE inhibitors may constitute a novel type of anti‐inflammatory agent. 1995 British Pharmacological Society