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]benzonitril
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- 作者：John A. Christopher ; Sarah J. Aves ; Kirstie A. Bennett ; Andrew S. Dor茅 ; James C. Errey ; Ali Jazayeri ; Fiona H. Marshall ; Krzysztof Okrasa ; Maria J. Serrano-Vega ; Benjamin G. Tehan ; Giselle R. Wiggin ; Miles Congreve
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：August 27, 2015
- 年：2015
- 卷：58
- 期：16
- 页码：6653-6664
- 全文大小：446K
- ISSN：1520-4804
文摘
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 脜, respectively.