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

doi:10.1016/j.bmcl.2011.06.118

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

School of Engineering & Physical Sciences

Research output: Contribution to journal › Article › peer-review

29 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 language	English
Pages (from-to)	5451-5456
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2011.06.118
Publication status	Published - 15 Sept 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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10.1016/j.bmcl.2011.06.118

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Ochiai, K., Ando, N., Iwase, K., Kishi, T., Fukuchi, K., Ohinata, A., Zushi, H., Yasue, T., Adams, D. R., & Kohno, Y. (2011). 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. Bioorganic and Medicinal Chemistry Letters, 21(18), 5451-5456. https://doi.org/10.1016/j.bmcl.2011.06.118

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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 = sep,

day = "15",

doi = "10.1016/j.bmcl.2011.06.118",

language = "English",

volume = "21",

pages = "5451--5456",

journal = "Bioorganic and Medicinal Chemistry Letters",

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Ochiai, K, Ando, N, Iwase, K, Kishi, T, Fukuchi, K, Ohinata, A, Zushi, H, Yasue, T, Adams, DR & Kohno, Y 2011, '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', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 18, pp. 5451-5456. https://doi.org/10.1016/j.bmcl.2011.06.118

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

Research output: Contribution to journal › Article › peer-review

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

SN - 0960-894X

VL - 21

SP - 5451

EP - 5456

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 18

ER -

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

Keywords

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