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)

被引：121

作者：

Christopher, John A. ^{[1
]}

Aves, Sarah J. ^{[1
]}

Bennett, Kirstie A. ^{[1
]}

Dore, Andrew S. ^{[1
]}

Errey, James C. ^{[1
]}

Jazayeri, Ali ^{[1
]}

Marshall, Fiona H. ^{[1
]}

Okrasa, Krzysztof ^{[1
]}

Serrano-Vega, Maria J. ^{[1
]}

Tehan, Benjamin G. ^{[1
]}

Wiggin, Giselle R. ^{[1
]}

Congreve, Miles ^{[1
]}

机构：

[1] Heptares Therapeut Ltd, Welwyn Garden City AL7 3AX, Herts, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 16期

关键词：

GLUTAMATE-RECEPTOR; 5; DOUBLE-BLIND; SAR; IDENTIFICATION; BASIMGLURANT; PHARMACOLOGY; INHIBITOR; EFFICACY; DESIGN; AFQ056;

D O I：

10.1021/acs.jmedchem.5b00892

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Fragment screening of a thermostabilized mGlu(5) 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 mGlu(5) receptor complexed with 25 and another molecule in the series, 14, were determined at resolutions of 2.6 and 3.1 angstrom, respectively.

引用

页码：6653 / 6664

页数：12