In vitro inhibition of arachidonic acid metabolism by two novel retinoid analogs.
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.
Fiedler-Nagy
C
C
Department of Allergy and Inflammation, Hoffmann-La Roche Inc., Nutley, NJ 07110.
Wittreich
B H
BH
Carey
M A
MA
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D066298:In Vitro Techniques; D008264:Macrophages / Q000378:metabolism; D008297:Male; D003012:Microbial Collagenase / Q000037:antagonists & inhibitors; D010529:Peritoneal Cavity / Q000166:cytology; D051381:Rats; D011919:Rats, Inbred Strains; D012176:Retinoids / Q000494:pharmacology*
D001095:Arachidonic Acids; D012176:Retinoids; D016718:Arachidonic Acid; D003012:Microbial Collagenase; D015232:Dinoprostone