Thein vivo antiinflammatory effects of (E)-2,6-bis(1,1-dimethylethyl)-4-[2-(5-methyl-1H-pyrazol-3-yl) ethenyl]phenol (PD 127443) a novel dual inhibitor of 5-lipoxygenase and cyclooxygenase

BF-389, dihydro-4-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-methyl-2H-1,2- oxazin-3(4H)-one, is a potent, orally active, antiarthritic and analgesic agent with low ulcerogenic potential. A comparison of the activity profiles of BF-389 and naproxen showed similarities in: (1) suppression of developing and chronic adjuvant arthritis (AA); (2) maximal inhibitory response, as shown by the E(max) values in the developing and established AA models; (3) inhibition of bone degenerative changes associated with chronic adjuvant arthritis; and (4) analgesic activity in the acetic acid and phenylquinone writhing assays. Though BF-389 has been shown to be a potent inhibitor of cyclooxygenase, IC50 = 0.84 +/- 0.25 microM against the production of PGE2 in vitro, there is a great difference from most cyclooxygenase inhibitors; it also inhibits the 5-lipoxygenase enzyme. For BF-389, the IC50 for in vitro LTB4 formation was found to be 3.65 +/- 1.19 microM. The ulcerogenic potential of BF-389 was compared to that of naproxen using a five-day in vivo ulcerogenic rat assay. The UD50 for naproxen was found to be approximately 30 mg/kg/day, p.o. Based upon efficacy in the DEV AA and EST AA models, UD50/ED50 values for naproxen were estimated to be 0.7 and 1.9, respectively. For BF-389 the UD50 was shown to be 520 (389-695) mg/kg/day, p.o., and the corresponding UD50/ED50 values were calculated to be 84 and 28, respectively, thus demonstrating the wide margin of safety between efficacy and ulcerogenicity in rats.

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1 5-Lipoxygenase Inhibitors and their Anti-inflammatory Activities

Batt

1992

Progress in Medicinal Chemistry

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Thein vivo antiinflammatory effects of (E)-2,6-bis(1,1-dimethylethyl)-4-[2-(5-methyl-1H-pyrazol-3-yl) ethenyl]phenol (PD 127443) a novel dual inhibitor of 5-lipoxygenase and cyclooxygenase

Cited by 3 publications

References 5 publications

Anti-inflammatory drugs: new multitarget compounds to face an old problem. The dual inhibition concept

Anti-inflammatory drugs: new multitarget compounds to face an old problem. The dual inhibition concept

Antiarthritic profile of BF-389 — A novel anti-inflammatory agent with low ulcerogenic liability

1 5-Lipoxygenase Inhibitors and their Anti-inflammatory Activities

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