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 SP - 836 LP - 845 DO - 10.1124/mol.115.099747 VL - 88 IS - 5 AU - Manna Huang AU - Yongxian Shao AU - Jianying Hou AU - Wenjun Cui 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 - 2015/11/01 UR - http://molpharm.aspetjournals.org/content/88/5/836.abstract N2 - Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)ethyl)amino)-1-cyclopentyl-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-day]pyrimidin-4-one [(S)-C33], has an IC50 value 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 the 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 with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors. ER -