Identification of 2,3-disubstituted pyridines as potent, non-emetic PDE4 inhibitors.

Autor: Kawasaki M; Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan., Fusano A; Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan. Electronic address: akira-fusano@ds-pharma.co.jp., Nigo T; Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan., Nakamura S; Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan., Ito MN; Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan., Teranishi Y; Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan., Matsumoto S; Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan., Toda H; Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan., Nomura N; Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan., Sumiyoshi T; Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan. Electronic address: t-sumiyo@kansai-u.ac.jp.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2014 Jun 15; Vol. 24 (12), pp. 2689-92. Date of Electronic Publication: 2014 Apr 20.
DOI: 10.1016/j.bmcl.2014.04.052
Abstrakt: A series of 2,3-disubstituted pyridines were synthesized as potential non-emetic PDE4 inhibitors. To decrease brain exposure and minimize emesis, we modified the lipophilic moiety of a series of emetic PDE4 inhibitors and found that introduction of a hydroxy group into the pyridine moiety of the side chain led to non-emetic compounds with preserved PDE4 inhibitory activity. Following optimization at the phenoxy group, we identified compound 1 as a potent non-emetic PDE4 inhibitor. Compound 1 showed significant efficacy in an animal model of asthma without inducing emesis.
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Databáze: MEDLINE
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