Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis

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• 作者：William D. Shipe ; Steven S. Sharik ; James C. Barrow ; Georgia B. McGaughey ; Cory R. Theberge ; Jason M. Uslaner ; Youwei Yan ; John J. Renger ; Sean M. Smith ; Paul J. Coleman ; Christopher D. Cox
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：October 8, 2015
• 年：2015
• 卷：58
• 期：19
• 页码：7888-7894
• 全文大小：572K
• ISSN：1520-4804

文摘

Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A K_i of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15h, with PDE10A K_i of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.