Use of Structure-Based Design to Discover a Potent, Selective, In Vivo Active Phosphodiesterase 10A Inhibitor Lead Series for the Treatment of Schizophrenia

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• 作者：Christopher J. Helal ; Zhijun Kang ; Xinjun Hou ; Jayvardhan Pandit ; Thomas A. Chappie ; John M. Humphrey ; Eric S. Marr ; Kimberly F. Fennell ; Lois K. Chenard ; Carol Fox ; Christopher J. Schmidt ; Robert D. Williams ; Douglas S. Chapin ; Judith Siuciak ; Lorraine Lebel ; Frank Menniti ; Julia Cianfrogna ; Kari R. Fonseca ; Frederick R. Nelson ; Rebecca O鈥機onnor ; Mary MacDougall ; Laura McDowell ; Spiros Liras
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 14, 2011
• 年：2011
• 卷：54
• 期：13
• 页码：4536-4547
• 全文大小：1213K
• 年卷期：v.54,no.13(July 14, 2011)
• ISSN：1520-4804

文摘

Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability.