ABSTRACT
A series of 1,6-naphthyridine-based compounds was synthesized as potent phosphodiesterase 10A (PDE10A) inhibitors. Structure-based chemical modifications of the discovered chemotype served to further improve potency and selectivity over DHODH, laying the foundation for future optimization efforts.
Subject(s)
Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacology , Naphthyridines/chemistry , Naphthyridines/pharmacology , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Humans , Models, Molecular , Nitriles/chemistry , Nitriles/pharmacology , Phosphoric Diester Hydrolases/chemistry , Structure-Activity RelationshipABSTRACT
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.