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

[Display omitted] 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 se...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2016-01, Vol.26 (1), p.197-202
Main Authors: Varnes, Jeffrey G., Geschwindner, Stefan, Holmquist, Christopher R., Forst, Janet, Wang, Xia, Dekker, Niek, Scott, Clay W., Tian, Gaochao, Wood, Michael W., Albert, Jeffrey S.
Format: Article
Language:English
Subjects:
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Fragment-assisted drug discovery
Fragment-based drug discovery
High-Throughput Screening Assays
Humans
Models, Molecular
Molecular Structure
PDE10A
Phosphodiesterase inhibitor
Phosphodiesterase Inhibitors - analysis
Phosphodiesterase Inhibitors - chemical synthesis
Phosphodiesterase Inhibitors - chemistry
Phosphodiesterase Inhibitors - pharmacology
Phosphoric Diester Hydrolases - metabolism
Schizophrenia
Structure-Activity Relationship
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Summary:[Display omitted] 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 ∼500μM), which were used to generate a hypothetical core scaffold. Application of this scaffold as a filter to HTS output afforded a 4μM hit, which, after preparation of a small number of analogs, was elaborated into a 16nM 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2015.10.100