Phosphodiesterase inhibitors. Part 1: Synthesis and structure-activity relationships of pyrazolopyridine-pyridazinone PDE inhibitors developed from ibudilast.

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Allcock RW, Blakli H, Jiang Z, Johnston KA, Morgan KM, Rosair GM, Iwase K, Kohno Y, Adams DR

Phosphodiesterase inhibitors. Part 1: Synthesis and structure-activity relationships of pyrazolopyridine-pyridazinone PDE inhibitors developed from ibudilast.

Bioorg Med Chem Lett. 2011 Jun 1;21(11):3307-12. doi: 10.1016/j.bmcl.2011.04.021. Epub 2011 Apr 13.

PubMed ID

21530250 [ View in PubMed

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Abstract

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(2H)-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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Ibudilast	cAMP-specific 3',5'-cyclic phosphodiesterase 4B	IC 50 (nM)	5000	N/A	N/A	Details
Ibudilast	cGMP-inhibited 3',5'-cyclic phosphodiesterase A	IC 50 (nM)	299000	N/A	N/A	Details