Phosphodiesterase inhibitors. Part 1: Synthesis and structure–activity relationships of pyrazolopyridine–pyridazinone PDE inhibitors developed from ibudilast
Ibudilast [1-(2-isopropylpyrazolo[1,5- a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone...
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Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2011-06, Vol.21 (11), p.3307-3312 |
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Hauptverfasser: | , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Ibudilast [1-(2-isopropylpyrazolo[1,5-
a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure–activity relationship exploration in the resulting 6-(pyrazolo[1,5-
a]pyridin-3-yl)pyridazin-3(2
H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4 inhibition is strongly promoted by introduction of a hydrophobic substituent at the pyridazinone N(2) centre and a methoxy group at C-7′ in the pyrazolopyridine. Migration of the pyridazinone ring connection from the pyrazolopyridine 3′-centre to C-4′ strongly enhances PDE4 inhibition. These studies establish a basis for development of potent PDE4-selective and dual PDE3/4-selective inhibitors derived from ibudilast. |
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ISSN: | 0960-894X 1464-3405 |
DOI: | 10.1016/j.bmcl.2011.04.021 |