2-Aryloxy-4-alkylaminopyridines: Discovery of Novel Corticotropin-Releasing Factor 1 Antagonists
详细信息 查看全文
- 作者：Yuhpyng L. Chen ; R. Scott Obach ; John Braselton ; Michael L. Corman ; James Forman ; Jody Freeman ; Randall J. Gallaschun ; Robert Mansbach ; Anne W. Schmidt ; Jeffrey S. Sprouse ; F. David Tingley ; III ; Eliz
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：March 13, 2008
- 年：2008
- 卷：51
- 期：5
- 页码：1385 - 1392
- 全文大小：132K
- 年卷期：v.51,no.5(March 13, 2008)
- ISSN：1520-4804
文摘
An orally active clinical candidate of corticotropin-releasing factor 1 (CRF1) antagonist 1 showed a significant positive food effect in dog and human after oral administration. Efforts to address the food effect issue led us to explore and discover compounds in series 2 as orally active CRF1 receptor antagonists, in which some compounds showed improved physicochemical properties while retaining desired pharmacological properties. Compound 3a (CP-376395) was selected for further development, due not only to its reduced food effects but also its greater efficacy in CNS models. Compound 3a was advanced to the clinic. The synthesis of representative potential candidates and their in vitro, ex vivo, and in vivo data are described.