3sn7

Highly Potent, Selective, and Orally Active Phosphodiestarase 10A Inhibitors

spinqualitylabelsall models 3sn7, resolution 1.82Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3sn7 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: 540, CL, MG, ZN Related: 3sni, 3snl Gene: PDE10A (HUMAN) 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 The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC(50) for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models. Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors.,Malamas MS, Ni Y, Erdei J, Stange H, Schindler R, Lankau HJ, Grunwald C, Fan KY, Parris K, Langen B, Egerland U, Hage T, Marquis KL, Grauer S, Brennan J, Navarra R, Graf R, Harrison BL, Robichaud A, Kronbach T, Pangalos MN, Hoefgen N, Brandon NJ J Med Chem. 2011 Oct 11. PMID:21988093 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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