Conversion of a cyclooxygenase (CO) inhibitor into a 5-lipoxygenase (LO) inhibitor: a general route to novel orally active anti-inflammatory and anti-allergy drugs.
Previously, the conversion of a CO inhibitor, naproxen, into an orally active 5-LO inhibitor, Wy-50,295, by covalent attachment of a quinoline group was reported. The authors now report the extension of this transformation to other CO inhibitors. Replacement of an existing substituent or a hydrogen in sulindac, etodolac, carprofen, diclofenac, oxaprozin, des-alpha-methyl-ketoprofen, or des-alpha-methyl-flurbiprofen by a methoxyquinoline group afforded new hybrid structures which were orally active 5-LO inhibitors in the rat RPAR (reverse passive Arthus reaction) assay. In contrast to Wy-50,295 which is a selective 5-LO inhibitor, some of these new hybrids were dual inhibitors of 5-LO and CO. For example, the quinoline-etodolac hybrid WAY-120,739, (1,8-diethyl-1,3,4,9-tetrahydro-6-(2-quinolinylmethoxy)pyrano [3,4-b]indole-1-acetic acid) was a dual inhibitor of 5-LO and CO (91% and 47% inhibition, respectively at 10 microM, rat PMN). In contrast, the quinoline-flurbiprofen hybrid WAY-121,006, (3-fluoro-4'-(2-quinolinylmethoxy)-[1,1'-biphenyl]-4-acetic acid), the quinoline-oxaprozin hybrid, WAY-120,460, (5-phenyl-4-[4-(2- quinolinylmethoxy)phenyl]-2-oxazolepropanoic acid) and the quinoline-carprofen hybrid WAY-120,429 (alpha-methyl-6-(2-quinolinylmethoxy)-9-(2-quinolinylmethoxy)-9H- carbazole-2-acetic acid) were purely 5-LO inhibitors (100%, 96% and 92% inhibition of 5-LO at 10 microM, rat PMN, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Kreft
A F
AF
Wyeth-Ayerst Research, Princeton, NJ.
Failli
A A
AA
Musser
J H
JH
Kubrak
D M
DM
Banker
A L
AL
Steffan
R
R
Demerson
C A
CA
Nelson
J A
JA
Shah
U S
US
Gray
W
W
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015777:Eicosanoids / Q000096:biosynthesis; D006168:Guinea Pigs; D006967:Hypersensitivity / Q000188:drug therapy; D015289:Leukotrienes / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009280:Naphthaleneacetic Acids / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology; D013189:SRS-A / Q000378:metabolism / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D009280:Naphthaleneacetic Acids; D011804:Quinolines; D013189:SRS-A; C067525:S(alpha)-methyl-6-(2-quinolinylmethoxy)-2-naphthaleneacetic acid