3-Hydroxy-5-trifluoromethyl-N-(2-(2-thienyl)-2-phenyl-ethenyl)- benzo (b) thiophene-2-carboxamide (L-652,343) is an inhibitor of cyclooxygenase and 5-lipoxygenase in vitro and inhibits the synthesis of the products of both these pathways in whole cells. L-652,343 is an inhibitor of the acute edema induced by carrageenan in vivo and is active topically in suppressing arachidonic acid induced inflammation in the skin. The compound is an effective inhibitor of the chronic inflammation of adjuvant and type II collagen induced polyarthritis. L-652,343 is an extremely potent analgesic in models of yeast and platelet activating factor induced hyperalgesia in rats and phenylbenzoquinone-induced writhing in mice. The fever induced by Brewer's yeast is lowered by L-652,343. The ulcerogenicity and gastric bleeding induced by L-652,343 is extremely low, providing a favorable therapeutic index which is superior to that of indomethacin, piroxicam and phenylbutazone.

A new class of tricyclic arylacetic acids was synthesized and evaluated as antiinflammatory/analgesic agents as well as inhibitors of prostaglandin synthetase. 11H-Dibenzo[b,e][1,4]dioxepin-2-, -3, -7, and -8-acetic and alpha-methylacetic acids and their derivatives were prepared by cyclization of diaryl ether precursors or by condensation of catechol and an aryl dihalide. The most potent compound in the carrageenan foot edema assay was alpha-methyl-11H-dibenzo[b,e][1,4]dioxepin-8-acetic acid (1 mg/kg = 43% inhibition). The most potent enzyme inhibitors were the 2-acetic acid and the alpha-methyl-7-acetic acid (IC50 = 0.1 microM). Some of these compounds were also found to be highly ulcerogenic.

Bioactive primary and secondary amines, when acylated with the Z-Gly-Phe group, are transported into pinocytic cells, such as macrophages, P-815 mastocytoma, SV-40 3T3, and leukemia 1210, much faster than the parent compounds. Amines such as lysosomotropic detergents [R. A. Firestone, J. M. Pisano, and R. J. Bonney, J. Med. Chem., 22, 1130 (1979) and nitrogen mustard, which are deactivated by acylation, are unmasked by enzymic action intracellularly, probably in lysosomes because an acidic pH maximum in activity exists which acts only on the L isomer. The added polarity and molecular weight brought about by acylation prevents the amines' normally facile entry into cells by simple diffusion, restricting it to an active-transport mechanism.