RT Journal Article
SR Electronic
T1 Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 836
OP 845
DO 10.1124/mol.115.099747
VO 88
IS 5
A1 Huang, Manna
A1 Shao, Yongxian
A1 Hou, Jianying
A1 Cui, Wenjun
A1 Liang, Beibei
A1 Huang, Yingchun
A1 Li, Zhe
A1 Wu, Yinuo
A1 Zhu, Xinhai
A1 Liu, Peiqing
A1 Wan, Yiqian
A1 Ke, Hengming
A1 Luo, Hai-Bin
YR 2015
UL http://molpharm.aspetjournals.org/content/88/5/836.abstract
AB 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.