Re-Discovering PDE3 Inhibitors - New Opportunities for a Long Neglected Target

Abstract

The PDE3 enzymes or "low Km cGMP-inhibited phosphodiesterases" have long been established as important mediators of cellular physiology, and synthetic PDE3 inhibitors have been critical to the delineation of the enzymes' roles. Yet despite decades of progress on the biology of these enzymes, the medicinal chemistry landscape relating to PDE3 inhibitors has remained essentially unchanged since the mid 1990's. Up until then the field was at the cutting edge of drug design; without the tools of molecular and structural biology, molecules of high potency were being achieved using logical pharmacophore models and lead modification. Yet virtually all the impetus went out of this area on the back of failures at the clinic and PDE3 as a therapeutic target largely fell out of favour. A decade later and with the "new" technologies of structural and molecular biology breathing new life into PDE3 research in general, PDE3 inhibitors are sought for target validation in an array of therapeutic applications. In this review, we examine the current state of PDE3 research; firstly we summarize the structural and functional properties of PDE3 enzymes with particular attention to the heterogeneity within this class of enzymes which differ markedly in expression, localisation and means of regulation across various tissue types. It is the structural and functional complexity of the PDE3 enzymes that underpins the re-emergence of PDE3s roles as targets for drug design. We then look at past clinical evaluation of PDE3 inhibitors that occurred without that information and which may have had a significant bearing on the outcome of those drug discovery efforts. Finally we look at current approaches to the design of PDE3 inhibitors which utilize that historic data but also incorporate new inputs from structural biology and combinatorial chemistry.

cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action

“…PDE5, whose presence in cardiomyocytes continues to be a matter of debate, is largely cytosolic and apparently more involved in breakdown of cytosolic cGMP pools generated by NO-GC activation (Palmer and Maurice, 2000;Corbin et al, 2005;Castro et al, 2006;Fischmeister et al, 2006;Lukowski et al, 2010). The catalytic activities of the PDE3 family have long been recognized as having important impact on lipolysis, glycogenolysis, insulin secretion, and cardiac function (Degerman et al, 1997;Thompson et al, 2007). PDE3 was the target of the first pharmacological agent (milrinone) approved for blocking PDE action (Seino et al, 1995).…”

Role of phosphodiesterases in the shaping of sub-plasma membrane cAMP oscillations and pulsatile insulin secretion

“…The PDE1 family of enzymes is activated by Ca 2+ -calmodulin (Goraya and Cooper, 2005), and cAMP hydrolysis by PDE2 is stimulated by cGMP. PDE3 is a dual-specificity enzyme with kinetic properties resulting in cGMP-inhibited cAMP degradation (Thompson et al, 2007;Murata et al, 2009). PDE4, PDE7 and PDE8 are all cAMPspecific enzymes.…”

Experimental and Theoretical Studies on the Tautomerism in 2-Aminopyridines and 2(1H)-Pyridinones: Synthesis of 2-Amino-4-aryl-3-cyano-6-(3,4-dimethoxyphenyl)pyridines and 4-Aryl-3-cyano-6-(3,4-dimethoxyphenyl)-2(1H)-pyridinones

“…PDE3 inhibitory, 8 cardiotonic, 5,9 and colon tumor cell growth inhibitory 10 effects. During past three decades, many synthetic methods have been used for the preparation of these 3-cyanopyridine, 1-6,11-14 and 3-cyanopyridinone derivatives.…”