The pharmacologic effects of 5-[3,5-bis(1,1-dimethylethyl)-4- hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione, choline salt (CI-986), a novel inhibitor of arachidonic acid metabolism in models of inflammation, analgesia and gastric irritation.

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.

Design of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3,4-thiadiazoles, -1,3,4-oxadiazoles, and -1,2,4-triazoles as orally-active, nonulcerogenic antiinflammatory agents.

To discover dual inhibitors of 5-lipoxygenase (LO) and cyclooxygenase (CO) with improved pharmacokinetic properties, we have designed and synthesized series of 1,2,4-triazole, 1,3,4-oxadiazole, and 1,3,4-thiadiazole di-tert-butylphenol derivatives which exhibit a wide range of log P (2.3 to > 4) and pKa (5.5-12) values. From this work 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)- thione, choline salt (12a, CI-986) was found to be a potent inhibitor of 5-LO (IC50 = 2.8 microM) and CO (IC50 = 0.8 microM), orally active in rat models of inflammation and nonulcerogenic.

Novel benzothiophene-, benzofuran-, and naphthalenecarboxamidotetrazoles as potential antiallergy agents.

The synthesis and antiallergic activity of a series of novel benzothiophene-, benzofuran-, and naphthalenecarboxamidotetrazoles are described. A number of the compounds inhibit the release of histamine from anti-IgE stimulated basophils obtained from allergic donors. Optimal inhibition is exhibited in benzothiophenes with a 3-alkoxy substituent in combination with a 5-methoxy, 6-methoxy, or a 5,6-dimethoxy group. Compound 13c (CI-959) also inhibited respiratory burst of human neutrophils and the release of mediators from anti-IgE-stimulated human chopped lung.

Novel thiophene-, pyrrole-, furan-, and benzenecarboxamidotetrazoles as potential antiallergy agents.

The synthesis and antiallergic activity of a series of novel thiophene-, pyrrole-, furan-, and benzenecarboxamidotetrazoles are described. A number of compounds inhibit the release of histamine from anti-IgE-stimulated human basophils. Optimal inhibition is exhibited in compounds with a 3-alkoxy, a 4-halo, and a 5-methyl, 5-methoxy, or 5-bromo on a thiophene-2-carboxamidotetrazole.

Antimicrobial and cytotoxic properties of 9,10-dihydrophenanthrenes: structure-activity studies on juncusol.

The antimicrobial and cytotoxic properties of a series of 9,10-dihydrophenanthrenes structurally related to juncusol (1a), a postulated phytoalexin with confirmed cytotoxic properties, are detailed. Two simple 9,10-dihydrophenanthrenes, 2,7-dihydroxy-3,8-dimethyl-9,10-dihydrophenanthrene (2h, desvinyljuncusol) and 2-hydroxy-3-methyl-9,10-dihydrophenanthrene (3h), were found to possess in vitro antimicrobial activity comparable with that of the natural product. Two 9,10-dihydrophenanthrenes substituted with quaternary ammonium salts, 2d and 3d, each containing a reactive benzylic dimethyl[(phenylthio)methyl]ammonio group, were found to be 10-20 times more potent than juncusol (1a). Confirmed in vitro cytotoxic activity that parallels antimicrobial activity was found for juncusol (1a), desvinyljuncusol (2h), 2-hydroxy-3-methyl-9,10-dihydrophenanthrene (3h), and the quaternary dimethyl[(phenylthio)methyl]ammonium salts 2d and 3d in a human lymphoblastic leukemia cell culture (CCRF-CEM, IC50 = nt, 9.3, nt, 0.9 and 1.4 microgram/mL, respectively), B-16 mouse melanoma cell culture (IC50 = 12.5, 17.5, 27.7, 0.3, and 0.5 microgram/mL, respectively), and L-1210 mouse lymphocytic leukemia cell culture (IC50 = 13.8, 10.2, 24.5, 1.3, and 3.7 micrograms/mL, respectively). The comparable potency and spectrum of activity of juncusol (1a), desvinyljuncusol (2h), and 2-hydroxy-3-methyl-9,10-dihydrophenanthrene (3h) suggest that the agents are acting as simple phenols in exerting their antimicrobial and cytotoxic effects.