Phosphodiesterase inhibitors. Part 3: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-dihydropyridazinones with anti-inflammatory and bronchodilatory activity

Koji Ochiai; Satoshi Takita; Tomohiko Eiraku; Akihiko Kojima; Kazuhiko Iwase; Tetsuya Kishi; Kazunori Fukuchi; Tokutaro Yasue; David R Adams; Robert W Allcock; Zhong Jiang; Yasushi Kohno

doi:10.1016/j.bmc.2012.01.033

Phosphodiesterase inhibitors. Part 3: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-dihydropyridazinones with anti-inflammatory and bronchodilatory activity

Koji Ochiai, Satoshi Takita, Tomohiko Eiraku, Akihiko Kojima, Kazuhiko Iwase, Tetsuya Kishi, Kazunori Fukuchi, Tokutaro Yasue, David R Adams, Robert W Allcock, Zhong Jiang, Yasushi Kohno

School of Engineering & Physical Sciences

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

47 Citations (Scopus)

Abstract

(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress histamine-induced bronchoconstriction and exhibit anti-inflammatory activity in vivo.

Original language	English
Pages (from-to)	1644-58
Number of pages	15
Journal	Bioorganic and Medicinal Chemistry
Volume	20
Issue number	5
DOIs	https://doi.org/10.1016/j.bmc.2012.01.033
Publication status	Published - 2012

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Ochiai, K., Takita, S., Eiraku, T., Kojima, A., Iwase, K., Kishi, T., Fukuchi, K., Yasue, T., Adams, D. R., Allcock, R. W., Jiang, Z., & Kohno, Y. (2012). Phosphodiesterase inhibitors. Part 3: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-dihydropyridazinones with anti-inflammatory and bronchodilatory activity. Bioorganic and Medicinal Chemistry, 20(5), 1644-58. https://doi.org/10.1016/j.bmc.2012.01.033

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title = "Phosphodiesterase inhibitors. Part 3: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-dihydropyridazinones with anti-inflammatory and bronchodilatory activity",

abstract = "(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress histamine-induced bronchoconstriction and exhibit anti-inflammatory activity in vivo.",

author = "Koji Ochiai and Satoshi Takita and Tomohiko Eiraku and Akihiko Kojima and Kazuhiko Iwase and Tetsuya Kishi and Kazunori Fukuchi and Tokutaro Yasue and Adams, {David R} and Allcock, {Robert W} and Zhong Jiang and Yasushi Kohno",

year = "2012",

doi = "10.1016/j.bmc.2012.01.033",

language = "English",

volume = "20",

pages = "1644--58",

journal = "Bioorganic and Medicinal Chemistry",

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Ochiai, K, Takita, S, Eiraku, T, Kojima, A, Iwase, K, Kishi, T, Fukuchi, K, Yasue, T, Adams, DR , Allcock, RW, Jiang, Z & Kohno, Y 2012, 'Phosphodiesterase inhibitors. Part 3: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-dihydropyridazinones with anti-inflammatory and bronchodilatory activity', Bioorganic and Medicinal Chemistry, vol. 20, no. 5, pp. 1644-58. https://doi.org/10.1016/j.bmc.2012.01.033

Phosphodiesterase inhibitors. Part 3: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-dihydropyridazinones with anti-inflammatory and bronchodilatory activity. / Ochiai, Koji; Takita, Satoshi; Eiraku, Tomohiko et al.
In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 5, 2012, p. 1644-58.

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

TY - JOUR

T1 - Phosphodiesterase inhibitors. Part 3: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-dihydropyridazinones with anti-inflammatory and bronchodilatory activity

AU - Ochiai, Koji

AU - Takita, Satoshi

AU - Eiraku, Tomohiko

AU - Kojima, Akihiko

AU - Iwase, Kazuhiko

AU - Kishi, Tetsuya

AU - Fukuchi, Kazunori

AU - Yasue, Tokutaro

AU - Adams, David R

AU - Allcock, Robert W

AU - Jiang, Zhong

AU - Kohno, Yasushi

PY - 2012

Y1 - 2012

N2 - (-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress histamine-induced bronchoconstriction and exhibit anti-inflammatory activity in vivo.

AB - (-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress histamine-induced bronchoconstriction and exhibit anti-inflammatory activity in vivo.

U2 - 10.1016/j.bmc.2012.01.033

DO - 10.1016/j.bmc.2012.01.033

M3 - Article

C2 - 22336247

VL - 20

SP - 1644

EP - 1658

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 5

ER -

Ochiai K, Takita S, Eiraku T, Kojima A, Iwase K, Kishi T et al. Phosphodiesterase inhibitors. Part 3: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-dihydropyridazinones with anti-inflammatory and bronchodilatory activity. Bioorganic and Medicinal Chemistry. 2012;20(5):1644-58. doi: 10.1016/j.bmc.2012.01.033