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)

Christopher, John A.; Aves, Sarah J.; Bennett, Kirstie A.; Doré, Andrew
S.; Errey, James C.; Jazayeri, Ali; Marshall, Fiona H.; Okrasa, Krzysztof; Serrano-Vega, Maria J.; Tehan, Benjamin G.; Wiggin, Giselle R.; Congreve, Miles

doi:10.1021/acs.jmedchem.5b00892.s001

jm5b00892_si_001.pdf (228.1 kB)

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)

journal contribution

posted on 2015-08-27, 00:00 authored by John A. Christopher, Sarah J. Aves, Kirstie A. Bennett, Andrew S. Doré, James C. Errey, Ali Jazayeri, Fiona H. Marshall, Krzysztof Okrasa, Maria J. Serrano-Vega, Benjamin G. Tehan, Giselle R. Wiggin, Miles Congreve

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.