Advances in targeting cyclic nucleotide phosphodiesterases

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) catalyse the hydrolysis of cyclic AMP and cyclic GMP, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signalling pathways and, consequently, myriad biological responses in health and disease. Currently, a small number of PDE inhibitors are used clinically for treating the pathophysiological dysregulation of cyclic nucleotide signalling in several disorders, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication and chronic obstructive pulmonary disease. However, pharmaceutical interest in PDEs has been reignited by the increasing understanding of the roles of individual PDEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways, by the structure-based design of novel specific inhibitors and by the development of more sophisticated strategies to target individual PDE variants.

Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors

“…4−6 PDE2 inhibition elevates levels of these molecules and could exert procognitive activity and restore hippocampal function, which are altered in disease states such as schizophrenia or Alzheimer's disease. 7 However, the lack of selective and brain penetrant PDE2 inhibitors has hampered validation of this hypothesis in animal models. We have previously reported the optimization of the poorly soluble HTS hit 1 into molecule 2 with combined PDE2/PDE10 activity (Scheme 1).…”

Pulmonary vascular changes in asthma and COPD

“…Vascular endothelial cells express variable levels of PDE-2, PDE-3, PDE-4, and PDE-5 in cells derived from 26 different sources aorta, umbilical vein, and microvascular structures [143]. Selective PDE inhibitors are used in the treatment of pulmonary hypertension [144], which make them interesting for treatment of also other pulmonary diseases with vascular involvements.…”

Selective inhibition of phosphodiesterases 4, 5 and 9 induces HSP20 phosphorylation and attenuates amyloid beta 1–42‐mediated cytotoxicity

“…There are 21 different genes that encode PDEs and these are separated functionally into 11 families depending on characteristics such as cyclic nucleotide specificity and modular structure 6. Further diversity is generated through multiple splice variants existing for a number of PDE families resulting in more than 60 different isoforms of PDE 6.…”