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Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile)

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Cite this: J. Med. Chem. 2015, 58, 16, 6653–6664
Publication Date (Web):July 30, 2015
https://doi.org/10.1021/acs.jmedchem.5b00892
Copyright © 2015 American Chemical Society
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    Abstract

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    Fragment screening of a thermostabilized mGlu5 receptor using a high-concentration radioligand binding assay enabled the identification of moderate affinity, high ligand efficiency (LE) pyrimidine hit 5. Subsequent optimization using structure-based drug discovery methods led to the selection of 25, HTL14242, as an advanced lead compound for further development. Structures of the stabilized mGlu5 receptor complexed with 25 and another molecule in the series, 14, were determined at resolutions of 2.6 and 3.1 Å, respectively.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.5b00892.

    • Supplier information or synthetic details for preparation of intermediates and final compounds, LCMS QC data for all compounds, NMR data for synthesized compounds, crystallographic information table, selectivity data for 25, HTL14242, ex vivo autoradiography and in vivo mouse marble burying experimental details (PDF)

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    Coordinates and structure factors have been deposited in the Protein Data Bank under the accession codes 5CGC (compound 14) and 5CGD (compound 25).

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