Abstract
The clinical significance of phosphodiesterase 5 (PDE5) inhibition is increasingly understood following the pioneering work with sildenafil, and the continuing development programmes for both sildenafil and other marketed inhibitors. Since the initial launch of sildenafil for male erectile dysfunction (MED), approval has now been granted for treatment of pulmonary hypertension, whilst ongoing studies have indicated the potential of PDE5 inhibition for the treatment of a range of additional indications including cardioprotection, memory retention and diabetes. Many of these additional indications are best suited to chronic oral dosing and emphasise the need for highly selective inhibitors with extended duration of action. This article will focus on a research programme aimed at the discovery of improved secondgeneration PDE5 inhibitors. Essential features of these new PDE5 inhibitors would be enhanced selectivity across the whole PDE family and pharmacokinetics compatible with once daily dosing. Key elements used in this programme are high throughput screening (HTS), exploitation of co-crystal structural information for bound inhibitor in the PDE5 active site, and employment of parallel chemistry to speed progress. Under the guidance of co-crystal structural information, a non-selective HTS hit with poor physicochemistry was initially modified using parallel chemistry to give a lead compound (3) that established a new PDE5 inhibitor series. Notably, (3) displayed physicochemistry compatible with a long plasma half-life, and wide chemical scope. Subsequent optimisation of (3) using crystal structure information to guide design, led rapidly to highly potent and selective PDE5 inhibitors (47, 50). Continued focus on physical properties through ligand efficiency evaluation and lipophilicity (cLogP), maintained the inherently desirable physicochemistry of the initial lead.
Keywords: high throughput screening (HTS), Sildenafil, 4-Methyl Pyridine-2-Amine, cGMP, alkoxy pocket
Current Topics in Medicinal Chemistry
Title: Design of Second Generation Phosphodiesterase 5 Inhibitors
Volume: 7 Issue: 4
Author(s): Michael J. Palmer, Andrew S. Bell, David N. A. Fox and David G. Brown
Affiliation:
Keywords: high throughput screening (HTS), Sildenafil, 4-Methyl Pyridine-2-Amine, cGMP, alkoxy pocket
Abstract: The clinical significance of phosphodiesterase 5 (PDE5) inhibition is increasingly understood following the pioneering work with sildenafil, and the continuing development programmes for both sildenafil and other marketed inhibitors. Since the initial launch of sildenafil for male erectile dysfunction (MED), approval has now been granted for treatment of pulmonary hypertension, whilst ongoing studies have indicated the potential of PDE5 inhibition for the treatment of a range of additional indications including cardioprotection, memory retention and diabetes. Many of these additional indications are best suited to chronic oral dosing and emphasise the need for highly selective inhibitors with extended duration of action. This article will focus on a research programme aimed at the discovery of improved secondgeneration PDE5 inhibitors. Essential features of these new PDE5 inhibitors would be enhanced selectivity across the whole PDE family and pharmacokinetics compatible with once daily dosing. Key elements used in this programme are high throughput screening (HTS), exploitation of co-crystal structural information for bound inhibitor in the PDE5 active site, and employment of parallel chemistry to speed progress. Under the guidance of co-crystal structural information, a non-selective HTS hit with poor physicochemistry was initially modified using parallel chemistry to give a lead compound (3) that established a new PDE5 inhibitor series. Notably, (3) displayed physicochemistry compatible with a long plasma half-life, and wide chemical scope. Subsequent optimisation of (3) using crystal structure information to guide design, led rapidly to highly potent and selective PDE5 inhibitors (47, 50). Continued focus on physical properties through ligand efficiency evaluation and lipophilicity (cLogP), maintained the inherently desirable physicochemistry of the initial lead.
Export Options
About this article
Cite this article as:
Palmer J. Michael, Bell S. Andrew, Fox N. A. David and Brown G. David, Design of Second Generation Phosphodiesterase 5 Inhibitors, Current Topics in Medicinal Chemistry 2007; 7 (4) . https://dx.doi.org/10.2174/156802607779941288
DOI https://dx.doi.org/10.2174/156802607779941288 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
-
Myogenic Properties of Brain and Cardiac Vessels and their Relation to Disease
Current Vascular Pharmacology QRPR and HCQRPQ, Two Peptides from Soybean, have an Inhibitory Effect on the Proliferation of HepG2 Cells
Protein & Peptide Letters Relationship Between Hypertension and Atherosclerosis: From a Viewpoint of the Most Potent Vasoconstrictor Human Urotensin II
Current Hypertension Reviews C-Peptide and its Correlation to Parameters of Insulin Resistance in the Metabolic Syndrome
CNS & Neurological Disorders - Drug Targets Antiangiogenic Therapy and Ovarian Cancer
Current Women`s Health Reviews Effects of Onion Extract on Endogenous Vascular H2S and Adrenomedulin in Rat Atherosclerosis
Current Pharmaceutical Biotechnology Calcific Aortic Stenosis: Molecular and Cellular Mechanisms, Medical Treatment Alternatives
Current Cardiology Reviews Impaired Renal Autoregulation in Susceptible Models of Renal Disease
Current Vascular Pharmacology Properties and Distribution of Angiotensin I Converting Enzyme
Current Pharmaceutical Design Effect of the Interaction Between Hypertension and Cerebral White Matter Changes on the Progression of Alzheimer Disease
Current Alzheimer Research Current Management of Peripheral Vascular Disease: Where is the Evidence?
Cardiovascular & Hematological Agents in Medicinal Chemistry Lithium and Kidney, 60 Years Later
Current Drug Safety Modulation of Heart Rate by Acute or Chronic Aerobic Exercise. Potential Effects on Blood Pressure Control
Current Pharmaceutical Design Glucocorticoid-Induced Hypertension and Tetrahydrobiopterin (BH4), a Common Cofactor for the Production of Vasoactive Molecules
Current Hypertension Reviews The Triad: Erectile Dysfunction - Endothelial Dysfunction - Cardiovascular Disease
Current Pharmaceutical Design Synthesis and Biological Activity of Prostaglandin Analogs Containing Heteroatoms in the Cyclopentane Ring
Current Organic Chemistry The Impact of Asymmetric Dimethylarginine (ADAMA), the Endogenous Nitric Oxide (NO) Synthase Inhibitor, to the Pathogenesis of Gastric Mucosal Damage
Current Pharmaceutical Design Editorial (Thematic Issue: Current Research, Knowledge and Controversies on High Density Lipoprotein)
Current Medicinal Chemistry State of the Art Management of Transfusion-Related Acute Lung Injury (TRALI)
Current Pharmaceutical Design Cardiovascular Effects of Coumarins Besides their Antioxidant Activity
Current Topics in Medicinal Chemistry