Abstract
(-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti-inflammatory agent. N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition. Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition. Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics. In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress histamine-induced bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration.
Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Inhalation
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Animals
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / chemistry*
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Anti-Inflammatory Agents / pharmacology
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Bronchoalveolar Lavage Fluid / cytology
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Bronchodilator Agents / chemical synthesis
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Bronchodilator Agents / chemistry*
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Bronchodilator Agents / pharmacology
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Cyclic Nucleotide Phosphodiesterases, Type 3 / chemistry
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Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism
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Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry
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Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
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Drug Design
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Leukocytes / drug effects
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Phosphodiesterase 3 Inhibitors / chemical synthesis
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Phosphodiesterase 3 Inhibitors / chemistry*
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Phosphodiesterase 3 Inhibitors / pharmacology
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Phosphodiesterase 4 Inhibitors / chemical synthesis
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Phosphodiesterase 4 Inhibitors / chemistry*
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Phosphodiesterase 4 Inhibitors / pharmacology
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Protein Binding
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Pyridazines / chemistry
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Pyridines / chemistry
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Rats
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Structure-Activity Relationship
Substances
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6-(7-methoxy-2-trifluoromethylpyrazolo(1,5-a)pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone
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Anti-Inflammatory Agents
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Bronchodilator Agents
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Phosphodiesterase 3 Inhibitors
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Phosphodiesterase 4 Inhibitors
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Pyridazines
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Pyridines
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Cyclic Nucleotide Phosphodiesterases, Type 3
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Cyclic Nucleotide Phosphodiesterases, Type 4