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.

Discovery of Potent Cyclic GMP Phosphodiesterase Inhibitors. 2-Pyridyl-and 2-Imidazolylquinazolines Possessing Cyclic GMP Phoshodiesterase and Thromboxane Synthesis Inhibitory Activities. -The structure of 2-phenyl-4-anilinoquinazoline, identified as moderate cyclic GMP phosphodiesterase (cGMP-PDE, PDE V) inhibitor, is modified ( ca. 70 examples) at the 2-, 4-, and 6-positions of the quinazoline ring, as demonstrated by derivatives of types (VII), (XI), (XIV), and ( XV). The 6-substituted quinazolines, e.g. (XVb) and (XVc), are 1000 times more potent with respect to their cGMP-PDE V inhibitory activity than the known inhibitor zaprinast. The cGMP-PDE inhibitors (VII), (XI) , and (XVa) also show thromboxane synthesis inhibitory activity. -(LEE, S. J.; KONISHI, Y.; YU, D. T.; MISKOWSKI, T. A.; RIVIELLO, C. M.; MACINA, O. T.; FRIERSON, M. R.; KONDO, K.; SUGITANI, M.; SIRCAR, J. C.; BLAZEJEWSKI, K. M.; J.