Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors

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• 作者：Michael S. Malamas ; Yike Ni ; James Erdei ; Hans Stange ; Rudolf Schindler ; Hans-Joachim Lankau ; Christian Grunwald ; Kristi Yi Fan ; Kevin Parris ; Barbara Langen ; Ute Egerland ; Thorsten Hage ; Karen L. Marquis ; Steve Grauer ; Julie Brennan ; Rachel Navarra ; Radka Graf ; Boyd L. Harrison ; Albert Robichaud ; Thomas Kronbach ; Menelas N. Pangalos ; Norbert Hoefgen ; Nicholas J. Brandon
• 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：7621-7638
• 全文大小：1218K
• 年卷期：v.54,no.21(November 10, 2011)
• ISSN：1520-4804

文摘

The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC₅₀ for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.