New cyclooxygenase-2/5-lipoxygenase inhibitors. 1. 7-tert-buty1-2,3-dihydro-3,3-dimethylbenzofuran derivatives as gastrointestinal safe antiinflammatory and analgesic agents: discovery and variation of the 5-keto substituent.
A series of 5-keto-substituted 7-tert-buty1-2,3-dihydro-3,3- dimethylbenzofurans (DHDMBFs) were prepared and evaluated as potential nonsteroidal antiinflammatory and analgesic agents. Interest in this class of compounds arose when a DHDMBF was found to be an active metabolite of the di-tert-butylphenol antiinflammatory agent tebufelone. We have now found that a variety of 5-keto-substituted DHDMBFs have good in vivo antiinflammatory and analgesic activity after oral administration. These compounds inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) in vitro. The cyclooxygenase inhibition was found to be selective for the cyclooxygenase-2 isoform, and this combination of COX-2/5-LOX inhibition may be responsible for the gastrointestinal safety of compounds such as 30.
Janusz
J M
JM
Procter & Gamble Pharmaceuticals, Health Care Research Center, Mason, Ohio 45040, USA.
Young
P A
PA
Ridgeway
J M
JM
Scherz
M W
MW
Enzweiler
K
K
Wu
L I
LI
Gan
L
L
Darolia
R
R
Matthews
R S
RS
Hennes
D
D
Kellstein
D E
DE
Green
S A
SA
Tulich
J L
JL
Rosario-Jansen
T
T
Magrisso
I J
IJ
Wehmeyer
K R
KR
Kuhlenbeck
D L
DL
Eichhold
T H
TH
Dobson
R L
RL
Sirko
S P
SP
Farmer
R W
RW
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002351:Carrageenan / Q000009:adverse effects; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D016859:Lipoxygenase Inhibitors; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley
D000893:Anti-Inflammatory Agents; D001572:Benzofurans; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D002351:Carrageenan