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ACS Med Chem Lett. 2014 Feb 22;5(5):527-32. doi: 10.1021/ml400519h. eCollection 2014 May 8.

New Hits as Antagonists of GPR103 Identified by HTS.

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CVMD Medicinal Chemistry, Discovery Sciences, and RIA Medicinal Chemistry, AstraZeneca , Pepparedsleden 1, 431 83 Mölndal, Sweden.


Preclinical data indicate that GPR103 receptor and its endogenous neuropeptides QRFP26 and QRFP43 are involved in appetite regulation. A high throughput screening (HTS) for small molecule GPR103 antagonists was performed with the clinical goal to target weight management by modulation of appetite. A high hit rate from the HTS and initial low confirmation with respect to functional versus affinity data challenged us to revise the established screening cascade. To secure high quality data while increasing throughput, the binding assay was optimized on quality to run at single concentration. This strategy enabled evaluation of a larger fraction of chemical clusters and singletons delivering 17 new compound classes for GPR103 antagonism. Representative compounds from three clusters are presented. One of the identified clusters was further investigated, and an initial structure-activity relationship study is reported. The most potent compound identified had a pIC50 of 7.9 with an improved ligand lipophilic efficiency.


26RFa; 43RFa; G-protein coupled receptor; GPCR; SP9155; appetite regulation; high throughput screening

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