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

Research output: Contribution to journalArticle

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

Cite this

Ochiai, Koji ; Ando, Naoki ; Iwase, Kazuhiko ; Kishi, Tetsuya ; Fukuchi, Kazunori ; Ohinata, Akira ; Zushi, Hitomi ; Yasue, Tokutaro ; Adams, David R. ; Kohno, Yasushi. / 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. In: Bioorganic and Medicinal Chemistry Letters. 2011 ; Vol. 21, No. 18. pp. 5451-5456.
@article{df32da38ddaf4a618fa60b82f0c76839,
title = "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",
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.",
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",
author = "Koji Ochiai and Naoki Ando and Kazuhiko Iwase and Tetsuya Kishi and Kazunori Fukuchi and Akira Ohinata and Hitomi Zushi and Tokutaro Yasue and Adams, {David R.} and Yasushi Kohno",
year = "2011",
month = "9",
day = "15",
doi = "10.1016/j.bmcl.2011.06.118",
language = "English",
volume = "21",
pages = "5451--5456",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "18",

}

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

In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 18, 15.09.2011, p. 5451-5456.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Ochiai, Koji

AU - Ando, Naoki

AU - Iwase, Kazuhiko

AU - Kishi, Tetsuya

AU - Fukuchi, Kazunori

AU - Ohinata, Akira

AU - Zushi, Hitomi

AU - Yasue, Tokutaro

AU - Adams, David R.

AU - Kohno, Yasushi

PY - 2011/9/15

Y1 - 2011/9/15

N2 - 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.

AB - 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.

KW - Cyclic 3 ',5 '-nucleotide phosphodiesterase (PDE)

KW - Ibudilast

KW - PDE3 inhibitors

KW - PDE4 inhibitors

KW - Respiratory disease

KW - OBSTRUCTIVE PULMONARY-DISEASE

KW - POSITIVE INOTROPIC AGENTS

KW - SLOW REACTING SUBSTANCE

KW - CHRONIC HEART-FAILURE

KW - PDE4 INHIBITORS

KW - CARDIOTONIC AGENTS

KW - HIGHLY POTENT

KW - IBUDILAST

KW - IDENTIFICATION

KW - ASTHMA

U2 - 10.1016/j.bmcl.2011.06.118

DO - 10.1016/j.bmcl.2011.06.118

M3 - Article

VL - 21

SP - 5451

EP - 5456

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 18

ER -