Discovery, Synthesis, and Structure鈥揂ctivity Relationship Development of a Series of N-4-(2,5-Dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): Characterization of a Novel Positive A

详细信息    查看全文

• 作者：Carrie K. Jones ; Darren W. Engers ; Analisa D. Thompson ; Julie R. Field ; Anna L. Blobaum ; Stacey R. Lindsley ; Ya Zhou ; Rocco D. Gogliotti ; Satyawan Jadhav ; Rocio Zamorano ; Jim Bogenpohl ; Yoland Smith ; Ryan Morrison ; J. Scott Daniels ; C. David Weaver ; P. Jeffrey Conn ; Craig W. Lindsley ; Colleen M. Niswender ; Corey R. Hopkins
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：November 10, 2011
• 年：2011
• 卷：54
• 期：21
• 页码：7639-7647
• 全文大小：379K
• 年卷期：v.54,no.21(November 10, 2011)
• ISSN：1520-4804

文摘

There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu₄). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood鈥揵rain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established antiparkinsonian model.