New cyclooxygenase-2/5-lipoxygenase inhibitors. 2. 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran derivatives as gastrointestinal safe antiinflammatory and analgesic agents: variations of the dihydrobenzofuran ring.
A series of 5-keto-substituted 7-tert-buty1-2,3-dihydro-3,3- dimethylbenzofurans (DHDMBFs) were found to be nonsteroidal antiinflammatory and analgesic agents. These compounds are inhibitors of 5-lipoxygenase (5-LOX) and cyclooxygenase (COX) with selectivity for the COX-2 isoform. A series of analogues were prepared to investigate the scope of this lead. Five ketone side chains from active DHDMBFs were used to investigate the effects of changes in the DHDMBF "core": the size and identity of the heterocycle and the substituent requirements of the heterocycle and phenyl ring. Biological testing showed that a variety of structural changes can be accommodated, but no structure was clearly superior to the DHDMBF structure.
Janusz
J M
JM
Procter & Gamble Pharmaceuticals, Health Care Research Center, Mason, Ohio 45040, USA.
Young
P A
PA
Scherz
M W
MW
Enzweiler
K
K
Wu
L I
LI
Gan
L
L
Pikul
S
S
McDow-Dunham
K L
KL
Johnson
C R
CR
Senanayake
C B
CB
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
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / 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; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley
D000700:Analgesics; D000893:Anti-Inflammatory Agents; D001572:Benzofurans; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D002351:Carrageenan