title: 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.
abstract: 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.
authors.affiliation: Procter & Gamble Pharmaceuticals, Health Care Research Center, Mason, Ohio 45040, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Janusz
authors.forename: P A
authors.initials: PA
authors.lastname: Young
authors.forename: J M
authors.initials: JM
authors.lastname: Ridgeway
authors.forename: M W
authors.initials: MW
authors.lastname: Scherz
authors.forename: K
authors.initials: K
authors.lastname: Enzweiler
authors.forename: L I
authors.initials: LI
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Gan
authors.forename: R
authors.initials: R
authors.lastname: Darolia
authors.forename: R S
authors.initials: RS
authors.lastname: Matthews
authors.forename: D
authors.initials: D
authors.lastname: Hennes
authors.forename: D E
authors.initials: DE
authors.lastname: Kellstein
authors.forename: S A
authors.initials: SA
authors.lastname: Green
authors.forename: J L
authors.initials: JL
authors.lastname: Tulich
authors.forename: T
authors.initials: T
authors.lastname: Rosario-Jansen
authors.forename: I J
authors.initials: IJ
authors.lastname: Magrisso
authors.forename: K R
authors.initials: KR
authors.lastname: Wehmeyer
authors.forename: D L
authors.initials: DL
authors.lastname: Kuhlenbeck
authors.forename: T H
authors.initials: TH
authors.lastname: Eichhold
authors.forename: R L
authors.initials: RL
authors.lastname: Dobson
authors.forename: S P
authors.initials: SP
authors.lastname: Sirko
authors.forename: R W
authors.initials: RW
authors.lastname: Farmer
mesh_terms: 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
chemical_list: D000893:Anti-Inflammatory Agents; D001572:Benzofurans; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D002351:Carrageenan