Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor

• Published in: Molecular pharmacology 2015-11, Vol.88 (5), p.836-845
• Main Authors: Huang, Manna, Shao, Yongxian, Hou, Jianying, Cui, Wenjun, Liang, Beibei, Huang, Yingchun, Li, Zhe, Wu, Yinuo, Zhu, Xinhai, Liu, Peiqing, Wan, Yiqian, Ke, Hengming, Luo, Hai-Bin
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-AMP Phosphodiesterases - chemistry; Amino Acid Sequence; Animals; Biological Availability; Drug Design; Humans; Hydrophobic and Hydrophilic Interactions; Male; Molecular Sequence Data; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacokinetics; Protein Multimerization; Rats; Rats, Sprague-Dawley; Stereoisomerism
• ISSN: 0026-895X; 1521-0111; 1521-0111
• DOI: 10.1124/mol.115.099747

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.