Synthesis of 1-(methanesulfonyl- and aminosulfonylphenyl)acetylenes that possess a 2-(N-difluoromethyl-1,2-dihydropyridin-2-one) pharmacophore: Evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity

Abstract

A hitherto unknown class of linear acetylene regioisomers were designed such that a SO(2)Me or SO(2)NH(2) group was located at the ortho-, meta- or para-position of the acetylene C-1 phenyl ring, and a N-difluoromethyl-1,2-dihydropyridin-2-one moiety was attached via its C-5 position to the C-2 position on an acetylene template (scaffold). All three SO(2)Me regioisomers, and the 4-SO(2)NH(2) analog, were potent inhibitors of 5-lipoxygenase (5-LOX IC(50)=3.2-3.5 microM range) relative to the reference drug caffeic acid (IC(50)=4.0 microM). The SO(2)Me regioisomers exhibited weak cyclooxygenease-1 (COX-1) and -2 (COX-2) inhibitory activity with a modest COX-2 selectivity index. The most potent 3-SO(2)Me, 4-SO(2)Me and 4-SO(2)NH(2) compounds, with respective ED(50) values of 66.1, 68.5 and 86.5 mg/kg po, exhibited comparable oral anti-inflammatory (AI) activity to that of the reference drug ibuprofen (ED(50)=67.4 mg/kg po). The N-difluoromethyl-1,2-dihydropyridin-2-one moiety provides a novel pharmacophore for the design of cyclic hydroxamic mimetics capable of inhibiting 5-LOX for exploitation in the development of 5-LOX inhibitory AI drugs.