Anti-inflammatory and safety profile of DuP 697, a novel orally effective prostaglandin synthesis inhibitor.
DuP 697 (5-bromo-2[4-fluorophenyl]-3-[4-methylsulfonylphenyl]-thiophene) is a potent inhibitor of paw swelling in nonestablished and established adjuvant arthritis in rats (ED50 = 0.03 and 0.18 mg/kg/day, respectively). DuP 697 had no effect on phenylquinone writhing in rats (ED50 greater than 100 mg/kg), but was analgetic against inflammation-related pain in the Randall-Selitto assay (ED30 = 3.5 mg/kg) and was a very potent antipyretic agent (ED50 = 0.05 mg/kg). The drug was not ulcerogenic in rats at single doses up to 400 mg/kg. DuP 697 (5 mg/kg i.v.) did not alter renal blood flow or the renal vascular response to angiotensin II in furosemide-pretreated, volume-depleted rats. In contrast, indomethacin (5 mg/kg i.v.) decreased renal blood flow and potentiated the renal vascular response to angiotensin II in these animals. DuP 697 was a moderate inhibitor of bull seminal vesicle prostaglandin (PG) synthesis (IC50 = 2.4 X 10(-5) M) and a potent inhibitor of rat brain PG synthesis (IC50 = 4.5 X 10(-6) M) but was ineffective against rat kidney PG synthesis (IC50 7.5 X 10(-5) M). These differential effects of DuP 697 on PG synthesis by various tissues may account for its high potency as an anti-inflammatory and antipyretic agent and its minimal toxicity profile.
Gans
K R
KR
Medical Products Department, E. I. du Pont de Nemours & Co., Inc., Wilmington, Delaware.
Galbraith
W
W
Roman
R J
RJ
Haber
S B
SB
Kerr
J S
JS
Schmidt
W K
WK
Smith
C
C
Hewes
W E
WE
Ackerman
N R
NR
D000284:Administration, Oral; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000633:toxicity; D002417:Cattle; D004064:Digestive System / Q000187:drug effects; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011453:Prostaglandins; D013876:Thiophenes; D000804:Angiotensin II; C064874:DuP 697