Phosphodiesterase inhibitors. Part 2: design, synthesis, and structure-activity relationships of dual PDE3/4-inhibitory pyrazolo[1,5-a]pyridines with anti-inflammatory and bronchodilatory activity.

Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 9107377 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3405 (Electronic) Linking ISSN: 0960894X NLM ISO Abbreviation: Bioorg Med Chem Lett Subsets: MEDLINE

Publication: Oxford : Elsevier Science Ltd
Original Publication: Oxford ; New York : Pergamon Press, c1991-

Drug Design*; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Bronchodilator Agents/*pharmacology ; Phosphodiesterase 3 Inhibitors/*pharmacology ; Phosphodiesterase 4 Inhibitors/*pharmacology ; Pyrazoles/*pharmacology ; Pyridines/*pharmacology; Animals ; Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis ; Anti-Inflammatory Agents, Non-Steroidal/chemistry ; Bronchodilator Agents/chemical synthesis ; Bronchodilator Agents/chemistry ; Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Guinea Pigs ; Molecular Structure ; Phosphodiesterase 3 Inhibitors/chemical synthesis ; Phosphodiesterase 3 Inhibitors/chemistry ; Phosphodiesterase 4 Inhibitors/chemical synthesis ; Phosphodiesterase 4 Inhibitors/chemistry ; Pyrazoles/chemical synthesis ; Pyrazoles/chemistry ; Pyridines/chemical synthesis ; Pyridines/chemistry ; Rats ; Stereoisomerism ; Structure-Activity Relationship

A structural survey of pyrazolopyridine-pyridazinone phosphodiesterase (PDE) inhibitors was made with a view to optimization of their dual PDE3/4-inhibitory activity for respiratory disease applications. These studies identified (-)-6-(7-methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridine-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490, compound 2ac) as a compound with potent combined bronchodilatory and anti-inflammatory activity and an improved therapeutic window over roflumilast.
(Copyright © 2011 Elsevier Ltd. All rights reserved.)

0 (Anti-Inflammatory Agents, Non-Steroidal)
0 (Bronchodilator Agents)
0 (Phosphodiesterase 3 Inhibitors)
0 (Phosphodiesterase 4 Inhibitors)
0 (Pyrazoles)
0 (Pyridines)
0 (pyrazolo(3,4-b)pyridine)
EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)
EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4)

Date Created: 20110719 Date Completed: 20111219 Latest Revision: 20110822

20221213

10.1016/j.bmcl.2011.06.118

21764304