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

Koji Ochiai, Naoki Ando, Kazuhiko Iwase, Tetsuya Kishi, Kazunori Fukuchi, Akira Ohinata, Hitomi Zushi, Tokutaro Yasue, David R. Adams, Yasushi Kohno

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19 Citations (Scopus)

Abstract

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. (C) 2011 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)5451-5456
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number18
DOIs
Publication statusPublished - 15 Sep 2011

Keywords

  • Cyclic 3 ',5 '-nucleotide phosphodiesterase (PDE)
  • Ibudilast
  • PDE3 inhibitors
  • PDE4 inhibitors
  • Respiratory disease
  • OBSTRUCTIVE PULMONARY-DISEASE
  • POSITIVE INOTROPIC AGENTS
  • SLOW REACTING SUBSTANCE
  • CHRONIC HEART-FAILURE
  • PDE4 INHIBITORS
  • CARDIOTONIC AGENTS
  • HIGHLY POTENT
  • IBUDILAST
  • IDENTIFICATION
  • ASTHMA

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