The perceived lack of drug discovery productivity in recent times has led to much debate in the pharmaceutical/biotechnology industry as escalating R&D costs are not being matched by increased output. Few observers doubt that selecting the right targets, i.e. those, which are critical to disease pathology and are 'druggable', is the best starting point for improved productivity.
The seven chapters of this volume describe recent progress towards drugs acting at a range of 'druggable' targets. One chapter addresses kinases, one covers an ion channel, two feature proteases and three of the chapters cover G-protein coupled receptors, which have historically perhaps been the most fruitful area for medicinal chemists.
It is increasingly apparent that productivity depends not only on the target selection, but also on the quality of the lead compounds. Good leads produce a double effect on productivity by reducing the downstream failure rate and also the timeline of a project. Chapter 1 provides an excellent review of the use of biostructures to find high-quality leads. The emphasis is on the kinase inhibitor field where there is an abundance of available biostructures. Technology for screening by X-ray crystallography and by NMR has advanced rapidly in recent years and in silico screening methods continue to improve. All three approaches are covered in this review.
The hepatitis C virus (HCV) is responsible for a world-wide epidemic with approximately 170 million people infected. It was identified only in the 1980s and since that time great efforts have been made in the search for treatments. Genetic analysis of the virus revealed coding for a serine protease (NS3) and the first clinical studies on inhibitors of the protease have recently been carried out. Chapter 2 presents a review of the medicinal chemistry approaches to this target.
The major successes in treating bacterial infections that were achieved by the antibiotics discovered in the middle part of the last century are now under severe threat from the emergence of resistant strains. Very few new classes of antibacterial have been created in the past 20 years. Peptide deformylase represents a new biochemical target and clinical candidates are beginning to emerge. Chapter 3 reviews progress to date.
The Transient Receptor Potential Vanilloid 1 (TRPV1) (vanilloid receptor 1) is a cation channel, which mediates the neuronal response to hot components of chilli peppers. Desensitisation using agonists provides a useful mechanism of pain control. Antagonists also show this effect and are reviewed in Chapter 4. They may find use in a range of clinical situations.
Ligands acting at histamine receptors have been a valuable source of medicines. The recent cloning of the H3 receptor has led to a resurgence of interest in the field. Several neurotransmitter systems are subject to modulation by neuronal H3 receptors and it is anticipated that the antagonists will be useful in the treatment of a range of diseases including narcolepsy and attention deficit hyperactivity disorder as well as improving cognition in situations such as Alzheimer's disease. Chapter 5 updates the medicinal chemistry of H3 receptor ligands which was last reviewed in this series in Volume 38.
The cannabinoid field was reviewed in Progress in Medicinal Chemistry Volume 35. Since that time great advances have been made in our understanding of cannabinoid receptor pharmacology. Many novel ligands have been discovered and several are expected to have exciting clinical utility. Medicinal chemistry approaches to the modulation of cannabinoid receptors are extensively reviewed in Chapter 6.
Preterm labour is the major cause of perinatal morbidity and mortality. Oxytocin antagonists offer an attractive approach to prevention. Chapter 7 reviews three decades of medicinal chemistry in this field. The peptide approach has resulted in valuable injectable products. Selectivity over the related vasopressin receptors and improvement in pharmacokinetic profile have been the key challenges for more recent non-peptide programmes, and these seem likely to yield orally available medicines.
List of Contributors ix
1 Finding Protein Kinase Hits using Structural Information 1
Mike Cherry, John Reader and David Williams
2 Blunting the Swiss Army Knife of Hepatitis C Virus: 65 Inhibitors of NS3/4A Protease
Peter W. White, Montse Llinas-Brunet and Michael Bos
3 Peptide Deformylase Inhibitors 109
Kelly Aubart and Magdalena Zalacain
4 Clinically Useful Vanilloid Receptor TRPV1 Antagonists: 145 Just around the Corner (or too Early to Tell)?
Giovanni Appendino and Arpad Szallasi
5 Recent Medicinal Chemistry of the Histamine H3 Receptor 181
Michael A. Letavic, Ann J. Barbier, Curt A. Dvorak and Nicholas I. Carruthers
6 Recent Progress in Cannabinoid Research 207
Julia Adam, Phillip M. Cowley, Takao Kiyoi, Angus J. Morrison and Christopher J.W. Mort
7 Oxytocin Antagonists as Potential Therapeutic Agents for the 331 Treatment of Preterm Labour
Michael J. Allen, David G.H. Livermore and Jacqueline E. Mordaunt
Subject Index 375
Author Index (Vols. 1-44) 379
Subject Index (Vols. 1-44) 385
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