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)