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 1990s. 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.
Keywords: cGMP-dependant protein kinases, cytosolic PDE3 isoforms, Saterinone, imidazoquinazolines, PDE3 Inhibitor Chemotypes
Current Topics in Medicinal Chemistry
Title: Re-Discovering PDE3 Inhibitors - New Opportunities for a Long Neglected Target
Volume: 7 Issue: 4
Author(s): Philip E. Thompson, Vincent Manganiello and Eva Degerman
Affiliation:
Keywords: cGMP-dependant protein kinases, cytosolic PDE3 isoforms, Saterinone, imidazoquinazolines, PDE3 Inhibitor Chemotypes
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 1990s. 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.
Export Options
About this article
Cite this article as:
Thompson E. Philip, Manganiello Vincent and Degerman Eva, Re-Discovering PDE3 Inhibitors - New Opportunities for a Long Neglected Target, Current Topics in Medicinal Chemistry 2007; 7 (4) . https://dx.doi.org/10.2174/156802607779941224
DOI https://dx.doi.org/10.2174/156802607779941224 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Adaptogens—History and Future Perspectives
Adaptogens are pharmacologically active compounds or plant extracts that are associated with the ability to enhance the body’s stability against stress. The intake of adaptogens is associated not only with a better ability to adapt to stress and maintain or normalise metabolic functions but also with better mental and physical ...read more
AlphaFold in Medicinal Chemistry: Opportunities and Challenges
AlphaFold, a groundbreaking AI tool for protein structure prediction, is revolutionizing drug discovery. Its near-atomic accuracy unlocks new avenues for designing targeted drugs and performing efficient virtual screening. However, AlphaFold's static predictions lack the dynamic nature of proteins, crucial for understanding drug action. This is especially true for multi-domain proteins, ...read more
Challenges, Consequences and Possible Treatments of Anticancer Drug Discovery ll
The use of several compounds has been the subject of increasing interest in phytochemistry, biochemistry, and other fields of research at the chemistry-biology-ecosystems interface. In spite of the continued search for new anticancer drugs, cancer remains a leading cause of death. Cancer mortalities are expected to increase to 12.9 million, ...read more
Chronic Kidney Disease
The scope of the special thematic issue includes but not limited to the mechanism of chronic kidney disease (CKD), the treatment of renal fibrosis and early diagnosis of CKD and so on. We also welcome manuscripts from other scientific research area with respect to internal medicine. Cell death has been ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Alzheimer Disease and Diabetes Mellitus: Do They have Anything in Common?
Current Alzheimer Research Mucopolysaccharidosis Type II (Hunter Syndrome): Clinical Picture and Treatment
Current Pharmaceutical Biotechnology COVID-19 related Complications during Pregnancy: A Systematic Review
New Emirates Medical Journal From Amino Acids to Proteins as Targets for Metal-based Drugs
Current Drug Metabolism Mitochondrial Therapeutics for Cardioprotection
Current Pharmaceutical Design Synthesis and Pharmacological Profile of an Orally-Active Growth Hormone Secretagogue, SM-130686
Combinatorial Chemistry & High Throughput Screening Endothelial Progenitor Cells and Vascular Biology in Diabetes Mellitus: Current Knowledge and Future Perspectives
Current Diabetes Reviews Safety of Systemic Biologic Agents in the Treatment of Non-malignant Skin Disorders
Current Drug Safety Evaluation and Management of Atrial Fibrillation
Cardiovascular & Hematological Disorders-Drug Targets Tako-tsubo Cardiomyopathy: A Review of the Literature
Current Cardiology Reviews Beyond Adding Years to Life: Health-related Quality-of-life and Functional Outcomes in Patients with Severe Aortic Valve Stenosis at High Surgical Risk Undergoing Transcatheter Aortic Valve Replacement
Current Cardiology Reviews Editorial (Hot Topic: Introduction to the Special Issue: Relevance of Endocrine and Metabolic Disorders in Heart Failure: From Pathophysiology to Therapeutic Approach)
Endocrine, Metabolic & Immune Disorders - Drug Targets Insights into the Role of Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Health and Disease
Current Chemical Biology Mitochondrial Diseases in Childhood
Current Molecular Medicine MicroRNA-34a Promotes Cardiomyocyte Apoptosis Post Myocardial Infarction Through Down-regulating Aldehyde Dehydrogenase 2
Current Pharmaceutical Design Proteome and Metabolome Alterations in Heart and Liver Indicate Compromised Energy Production During Sepsis
Protein & Peptide Letters Unravelling the Role of Infectious Agents in the Pathogenesis of Human Autoimmunity: The Hypothesis of the Retroviral Involvement Revisited
Current Molecular Medicine Potential Therapeutic Targets in Cirrhotic Cardiomyopathy
Cardiovascular & Hematological Disorders-Drug Targets Rheumatoid Arthritis: Cardiovascular Manifestations, Pathogenesis, and Therapy
Current Pharmaceutical Design Current Status of Anti-Picornavirus Therapies
Current Pharmaceutical Design