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

详细信息    查看全文

• 作者：Motoji Kawasaki ; Akira Fusano ; ^{akira-fusano@ds-pharma.co.jp" class="auth_mail} ; Tomohiro Nigo ; Shunya Nakamura ; Mari N. Ito ; Yasuhiro Teranishi ; Satoshi Matsumoto ; Hiroshi Toda ; Naruaki Nomura ; Takaaki Sumiyoshi ; ^&dagger ; ; ^{t-sumiyo@kansai-u.ac.jp" class="auth_mail}
• 关键词：Phosphodiesterase 4 ; PDE4 inhibitors ; 2 ; 3-Disubstituted pyridine ; Structure activity relationship ; Anti-inflammatory agent
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：15 June 2014
• 年：2014
• 卷：24
• 期：12
• 页码：2689-2692
• 全文大小：778 K

文摘

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.