Application of Structure-Based Drug Design and Parallel Chemistry to Identify Selective, Brain Penetrant, In Vivo Active Phosphodiesterase 9A Inhibitors

详细信息    查看全文

• 作者：Michelle M. Claffey ; Christopher J. Helal ; Patrick R. Verhoest ; Zhijun Kang ; Kristina S. Fors ; Stanley Jung ; Jiaying Zhong ; Mark W. Bundesmann ; Xinjun Hou ; Shenping Lui ; Robin J. Kleiman ; Michelle Vanase-Frawley ; Anne W. Schmidt ; Frank Menniti ; Christopher J. Schmidt ; William E. Hoffman ; Mihaly Hajos ; Laura McDowell ; Rebecca E. O鈥機onnor ; Mary MacDougall-Murphy ; Kari R. Fonseca ; Stacey L. Becker ; Frederick R. Nelson ; Spiros Liras
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：55
• 期：21
• 页码：9055-9068
• 全文大小：588K
• 年卷期：v.55,no.21(November 8, 2012)
• ISSN：1520-4804

文摘

Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer鈥檚 disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma 鈮? in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF.