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

Molecular Pharmacology
Manna HuangHai-Bin Luo

Abstract

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.

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Citations

Nov 14, 2016·Brazilian Journal of Microbiology : [publication of the Brazilian Society for Microbiology]·Angela Faustino JozalaAdalberto Pessoa
Jul 28, 2020·BioMed Research International·Samuele MaramaiSamir Yahiaoui
Jan 8, 2021·European Journal of Medicinal Chemistry·Nathalia Fonseca NadurArthur Eugen Kümmerle
Feb 17, 2021·ChemMedChem·Clinton G L Veale
Mar 27, 2018·European Journal of Medicinal Chemistry·Ting PengJianyou Shi
Jan 25, 2018·Journal of Medicinal Chemistry·Yinuo WuHai-Bin Luo

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