Ro 23-6457, (all-E)-3,7-dimethyl-9-[2-(trifluoromethyl)-6-(nonyloxy)phenyl]-2, 4,6,8- nonatetraenoic
acid, and
Ro 23-2895, (all-E)-9-[2-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraen oic
acid, are two novel
retinoid analogs which exhibit antiinflammatory activity in both the developing and the established rat
adjuvant arthritis models [8]. Here we investigated the effect of these two compounds on the production of
arachidonic acid (AA) metabolites in two in vitro test systems [i.e., Ca2+
ionophore A23187 (I)-stimulated resident rat peritoneal macrophages (MO) and
cytokine-stimulated human dermal fibroblasts (HDF)]. Both compounds,
Ro 23-6457 and
Ro 23-2895, significantly inhibited the release of 14C-AA metabolites and the production of
LTB4,
PGE2, and
6-keto-PGF1 alpha in I-stimulated MO, at concentrations of 1-33 microM. Both compounds also inhibited the production of
PGE2 in HDF stimulated by either rhuIL-1 alpha or huTNF alpha at concentrations of 1 x 10(-5) to 1 x 10(-7) M.
Ro 23-2895 was also a potent inhibitor of IL-1-induced
collagenase production in rheumatoid synovial cells (IC50 approximately 1 to 2.5 x 10(-8) M). The inhibitory profile of these novel compounds in these cell systems is therefore similar to that of other known antiinflammatory
retinoids (e.g., all-trans- and 13-cis-retinoic acid). Inhibitory effects such as those described here might in part contribute to the antiinflammatory activity of these compounds in vivo.