4bbx

Discovery of a potent, selective and orally active PDE10A inhibitor for the treatment of schizophrenia

spinqualitylabelsall models 4bbx, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4bbx is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: LKF, MG, ZN Related: 1lrb, 2wey, 2y0j, 4ael, 4ajd, 4ajf, 4ajg, 4ajm Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [PDE10_HUMAN] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate. Publication Abstract from PubMed We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high throughput screening (HTS) campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a methoxyethylpyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure-activity- and structure-properties-relationships (SAR and SPR) resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and good pharmacokinetic profile in rats. Discovery of a potent, selective and orally active PDE10A inhibitor for the potential treatment of schizophrenia.,Bartolome-Nebreda JM, Delgado F, Martin ML, Martinez-Viturro CM, Pastor J, Tong HM, Iturrino L, Macdonald GJ, Sanderson WE, Megens A, Langlois X, Somers M, Vanhoof G, Conde Ceide S J Med Chem. 2014 Apr 23. PMID:24758746 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphodiesterase

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