Bioorganic & Medicinal Chemistry Letters 2011-01-01

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

Robert W. Allcock, Haakon Blakli, Zhong Jiang, Karen A. Johnston, Keith M. Morgan, Georgina M. Rosair, Kazuhiko Iwase, Yasushi Kohno, David R. Adams, Robert W. Allcock, Haakon Blakli, Zhong Jiang, Karen A. Johnston, Keith M. Morgan, Georgina M. Rosair, Kazuhiko Iwase, Yasushi Kohno, David R. Adams, Robert W. Allcock, Haakon Blakli, Zhong Jiang, Karen A. Johnston, Keith M. Morgan, Georgina M. Rosair, Kazuhiko Iwase, Yasushi Kohno, David R. Adams

Index: Bioorg. Med. Chem. Lett. 21(11) , 3307-12, (2011)

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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.Copyright © 2011 Elsevier Ltd. All rights reserved.