TY - JOUR T1 - Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.115.099747 SP - mol.115.099747 AU - Manna Huang AU - Yongxian Shao AU - Jianying Hou AU - Wenjun Cai AU - Beibei Liang AU - Yingchun Huang AU - Zhe Li AU - Yinuo Wu AU - Xinhai Zhu AU - Peiqing Liu AU - Yiqian Wan AU - Hengming Ke AU - Hai-Bin Luo Y1 - 2015/01/01 UR - http://molpharm.aspetjournals.org/content/early/2015/08/27/mol.115.099747.abstract N2 - Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of CNS diseases and diabetes. Here we report discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound (S)-C33 has IC50 of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not (R)-C33 and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and different interactions of C33 enantiomers imply a necessity of consideration of the whole PDE9 dimer for design of inhibitors. ER -