Antiarthritic profile of BF-389--a novel anti-inflammatory agent with low ulcerogenic liability.
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.
Wong
S
S
Biofor Limited, Waverly, PA.
Lee
S J
SJ
Frierson
M R
MR
Proch
J
J
Miskowski
T A
TA
Rigby
B S
BS
Schmolka
S J
SJ
Naismith
R W
RW
Kreutzer
D C
DC
Lindquist
R
R
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D001169:Arthritis, Experimental / Q000188:drug therapy; D004195:Disease Models, Animal; D004487:Edema / Q000188:drug therapy; D005260:Female; D008297:Male; D051379:Mice; D010078:Oxazines / Q000494:pharmacology*; D010147:Pain Measurement; D010437:Peptic Ulcer / Q000139:chemically induced; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010078:Oxazines; D010636:Phenols; C072260:Biofor 389; D016718:Arachidonic Acid