Efficacious Inhaled PDE4 Inhibitors with Low Emetic Potential and Long Duration of Action for the Treatment of COPD
详细信息 查看全文
- 作者：Chris De Savi ; Rhona J. Cox ; Daniel J. Warner ; Anthony R. Cook ; Mark R. Dickinson ; Amy McDonough ; Louis C. Morrill ; Beth Parker ; Glen Andrews ; Simon S. Young ; Peter S. Gilmour ; Rob Riley ; Matthew S. Dearman
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：June 12, 2014
- 年：2014
- 卷：57
- 期：11
- 页码：4661-4676
- 全文大小：731K
- 年卷期：v.57,no.11(June 12, 2014)
- ISSN：1520-4804
文摘
Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential.