Fragment-assisted hit investigation involving integrated HTS and fragment screening: Application to the identification of phosphodiesterase 10A (PDE10A) inhibitors

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• 作者：Jeffrey G. Varnes^a ; ^{jeffrey.varnes@astrazeneca.com" class="auth_mail" title="E-mail the corresponding author} ; Stefan Geschwindner^b ; Christopher R. Holmquist^a ; Janet Forst^a ; Xia Wang^a ; Niek Dekker^b ; Clay W. Scott^a ; Gaochao Tian^a ; Michael W. Wood^a ; Jeffrey S. Albert^a ; ^{jeffrey.albert@intellisynrd.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：PDE10A ; Fragment-based drug discovery ; Fragment-assisted drug discovery ; Phosphodiesterase inhibitor ; Schizophrenia
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 January 2016
• 年：2016
• 卷：26
• 期：1
• 页码：197-202
• 全文大小：1673 K

文摘

Fragment-based drug design (FBDD) relies on direct elaboration of fragment hits and typically requires high resolution structural information to guide optimization. In fragment-assisted drug discovery (FADD), fragments provide information to guide selection and design but do not serve as starting points for elaboration. We describe FADD and high-throughput screening (HTS) campaign strategies conducted in parallel against PDE10A where fragment hit co-crystallography was not available. The fragment screen led to prioritized fragment hits (IC₅₀’s ∼500 μM), which were used to generate a hypothetical core scaffold. Application of this scaffold as a filter to HTS output afforded a 4 μM hit, which, after preparation of a small number of analogs, was elaborated into a 16 nM lead. This approach highlights the strength of FADD, as fragment methods were applied despite the absence of co-crystallographical information to efficiently identify a lead compound for further optimization.