Phosphodiesterase inhibitors. Part 2: Design, synthesis, and structure-activity relationships of dual PDE3/4-inhibitory pyrazolo[1,5-a]pyridines with anti-inflammatory and bronchodilatory activity |
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| Authors: | Koji OchiaiNaoki Ando Kazuhiko IwaseTetsuya Kishi Kazunori FukuchiAkira Ohinata Hitomi ZushiTokutaro Yasue David R. AdamsYasushi Kohno |
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| Affiliation: | a Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd, 2399-1 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan
b Chemistry Department, School of Engineering and Physical Sciences, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, United Kingdom |
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| Abstract: | A structural survey of pyrazolopyridine-pyridazinone phosphodiesterase (PDE) inhibitors was made with a view to optimization of their dual PDE3/4-inhibitory activity for respiratory disease applications. These studies identified (−)-6-(7-methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridine-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490, compound 2ac) as a compound with potent combined bronchodilatory and anti-inflammatory activity and an improved therapeutic window over roflumilast. |
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| Keywords: | Cyclic 3&prime ,5&prime -nucleotide phosphodiesterase (PDE) Ibudilast PDE3 inhibitors PDE4 inhibitors Respiratory disease |
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