title: Phosphodiesterase inhibitors. Part 1: Synthesis and structure-activity relationships of pyrazolopyridine-pyridazinone PDE inhibitors developed from ibudilast.
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.
authors.affiliation: Chemistry Department, School of Engineering and Physical Sciences, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, United Kingdom.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Allcock
authors.forename: Haakon
authors.initials: H
authors.lastname: Blakli
authors.forename: Zhong
authors.initials: Z
authors.lastname: Jiang
authors.forename: Karen A
authors.initials: KA
authors.lastname: Johnston
authors.forename: Keith M
authors.initials: KM
authors.lastname: Morgan
authors.forename: Georgina M
authors.initials: GM
authors.lastname: Rosair
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Iwase
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kohno
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
mesh_terms: D001665:Binding Sites; D004789:Enzyme Activation / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013722:Teprotide / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007212:Indolizines
chemical_list: D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; D011725:Pyridines; D013722:Teprotide; C118531:pyrazolopyridine; C038366:ibudilast; D007212:Indolizines