Discovery of a Novel Class of Phosphodiesterase 10A Inhibitors and Identification of Clinical Candidate 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for

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• 作者：Patrick R. Verhoest ; Douglas S. Chapin ; Michael Corman ; Kari Fonseca ; John F. Harms ; Xinjun Hou ; Eric S. Marr ; Frank S. Menniti ; Frederick Nelson ; Rebecca O’ ; Connor ; Jayvardhan Pandit ; Caroline P
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：August 27, 2009
• 年：2009
• 卷：52
• 期：16
• 页码：5188-5196
• 全文大小：998K
• 年卷期：v.52,no.16(August 27, 2009)
• ISSN：1520-4804

文摘

By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique “selectivity pocket” for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.