Abstract: Matrix metalloproteinases (MMPs) are involved in the normal processes of tissue remodelling and repair, but have increasingly been implicated in a range of disease states where they are over-expressed. This review summarises developments in the design and clinical evaluation of synthetic MMP inhibitors since the subject was last covered in this journal in 1995.

Abstract: The treatment of anxiety disorders remains an active area of research. Behavioural tests developed in the 1960s have been augmented by specific receptor binding assays. Selective modulation of these binding sites offers the hope that the abuse liability, sedation and ethanol interaction found with earlier drugs can be removed entirely or in part. Although most anxiolytic drug discovery continues to be centred on the neurotransmitters γ-aminobutyric acid (GABA) and serotonin (5-HT), research in other areas such as those involving cholecystokinin (CCK), corticotrophin releasing factor (CRF) and neuropeptide Y (NPY) also has promise for the future. This article reviews the primary and patent literature in the anxiolytic area for 1994 to the present.

Abstract: In this article, we update the progress reported towards developing an inhibitor of protein farmesyltransferase (PFTase) as a new type of cancer therapy. For the rationale behind this undertaking, please refer to the review published in this journal in December 1995 [1], and other reviews [2,3]. A few experiments bearing on the utility of PFTase inhibitors as antitumour agents are considered first, including biological results obtained with compounds described in our earlier review. Finally, new compounds described in the scientific and patent literature in the past year are reported. As in the previous review, these are grouped according to their kinetic mechanism of inhibition of PFTase.

Abstract: This review article examines the role of supervised and unsupervised artificial neural networks (ANNs) in the field of quantitative structure-activity relationships (QSAR). They were found to be useful in both classical QSAR and structure-property correlation (SPC) studies where the data sets contain significant non-linear relationships. New applications of ANNs, including methods of descriptor optimisation, simultaneous prediction of multiple descriptors, the development of flexible pharmacophore models and new methods for the multidimensional reduction and display of data sets suggest that ANNs will have a useful role in the field of QSAR in the future.

Abstract: There has been prolific patenting activity surrounding antisense technology to date. With more than fifty issued patents and innumerable applications published, a relatively clear picture about current and future patent positions can be defined. In this article the basics of antisense patenting, various strategies and the current patent positions of the major antisense programs are reviewed.

Abstract: Quinolones, such as ciprofloxacin and ofloxacin, have gained wide acceptance for the treatment of bacterial infections of the respiratory tract, urinary tract, skin and soft tissues, as well as sexually transmitted diseases. Good pharmacokinetic profiles and potent activities against a wide range of Gram-negative and Gram-positive pathogens result in the use of these antibacterials in both hospital and community settings. Although recently developed clinical quinolones dominate in the chemotherapy of various bacterial infections, their use is restricted by limited activities against a number of clinically-important Gram-positive bacteria such as Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and enterococci. Ciprofloxacin, the market leader, also has low potency against anaerobes. Bacterial resistance (such as in Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus) to ciprofloxacin is increasing rapidly. Many quinolone compounds are being synthesised to address...

Abstract: The area of neurokinin (NK) research has seen an explosion of interest following the identification of the first non-peptide antagonists. Since then nearly every major pharmaceutical company has reported work in this area, describing a wide variety of different chemical series. The early preclinical models suggest a number of potential clinical utilities including analgesia, anxiety, arthritis, asthma, emesis, migraine and schizophrenia. This patent update addresses the trends in the patenting of NK1, NK2 and NK3 receptor antagonists between 1990 and 1995, focussing on advances made since the last review in 1993, and identifies and evaluates the key compounds under the research spotlight.

Abstract: The development of single molecules which possess the ability to inhibit both of the membrane-bound zinc metalloproteases, angiotensin-converting enzyme EC 2.4.15.1 (ACE) and neutral endopeptidase EC 3.4.24.11 (NEP), has been the focus of much recent drug discovery effort. These agents represent a new class of cardiovascular agent that should be more effective in treating a broader range of hypertensive patient and in congestive heart failure (CHF). Dual ACE and NEP inhibitors are currently under clinical investigation for hypertension and CHF and several more are under preclinical study. This review focuses on ACE/NEP dual inhibitors reported in the patent and primary literature over the past four years.

Abstract: Antagonists of the serotonin 5-HT3 receptor are clinically effective antinausea and anti-emetic drugs for the treatment of cancer patients undergoing chemotherapy and for patients undergoing procedures involving general anaesthesia. These compounds have also been evaluated for the treatment of irritable bowel syndrome, other painrelated disorders (including migraine) and a variety of central nervous system disorders (including anxiety, psychosis and the treatment of drug abuse). The status of research into potential clinical applications of these drugs is evaluated in this review. The evidence from preclinical and clinical studies is compared and avenues for future drug development using these compounds are discussed.

Abstract: Glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists have been shown to be effective in reducing the rate of ischaemic complications due to pathophysiological conditions such as atherosclerosis or coronary intervention. This review will cover all patenting activity in this now mature field of research up to and including August 1996, and will focus on the more significant patents and patent applications.

Abstract: Our ability to genetically modify antibody molecules has been dramatically enhanced by a number of technological breakthroughs, including the ability to rapidly and easily clone the variable region genes, and the development of good expression systems. In addition phage display technology has given a new impetus to the field by allowing the isolation and modification of novel antibodies. This paper reviews these important areas, and describes some of the more common genetic constructs that have been produced. Such recombinant molecules are entering clinical trials more frequently and will become increasingly important as diagnostic and therapeutic agents.

Abstract: Leukotriene B4 (LTB4), a product of the arachidonic acid cascade, has been shown to be an important modulator of inflammatory cell function, the overproduction of which is believed to potentiate the tissue damage seen in many inflammatory diseases where medical needs remain unmet. Several antagonists of the LTB4 receptor are poised for clinical trial and a new spate of third generation compounds has been revealed in the recent patent literature.

Abstract: Traditional, non-steroidal anti-inflammatory agents (NSAIAs) are arachidonate metabolite related. Since arachidonate metabolites do not induce the whole range of inflammatory responses, their blockade does not produce anti-inflammatory actions as potent as those of the corticosteroids. The recent development of cytokine research reveals the wide range involvement of IL-1, IL-6 and tumour necrosis factor (TNF) in the inflammatory process. Therefore, cytokine antagonists produce the most effective means of treatment for inflammatory disorders and are as effective, or even more potent, than corticosteroids, without producing the side effects common to such compounds. The only IL-1 blocker available today is the natural IL-1 receptor antagonist (IL-1 RA), a polypeptide which is easily metabolised in the bloodstream with a very short half-life (21 minutes). Thus, active research has been carried out to develop stable, long-acting agents which can be taken by oral administration or by parenteral injections rath...

Abstract: The advent of combinatorial chemistry in all its manifestations has the potential to change radically the patenting strategies of all pharmaceutical organisations. This editorial reviews recent progress over the past three years.

Abstract: While early experience with D1 receptor agonists in Parkinson's disease (PD) was disappointing, more recent work, especially in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian monkeys, has shown that D1 selective receptor agonists and dopamine reuptake blockers (themselves likely to influence motor systems predominantly through D1-mediated mechanisms), have powerful antiparkinsonian effects and may also effectively combat common complications of current treatment, such as L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias.

Abstract: This patent update relates to agents for the treatment of neurodegenerative diseases, for both the peripheral and central nervous systems Selected patent activities are described and summarised below for the period of January through June 1996 The newly disclosed agents are listed by their actual or proposed biological mechanism While many patent applications include agents for the treatment of neurodegenerative diseases, this review cites only those patents which either disclose biological data to support potential activity, display novel structures or claim relatively unexplored mechanisms for neuroprotection

Abstract: Azole antifungal agents are used extensively throughout the world due to their excellent antifungal activity and low toxicity. However, improvements are needed in their spectra, potency and pharmaco-kinetic properties. Current research efforts are being directed towards overcoming these problems through the development of new, improved azole compounds. This article describes recent advances in the development of azole antifungal agents following on from fluconazole (FLCZ) and itraconazole (ITCZ).

Abstract: Metabotropic glutamate (mGlu) receptors are becoming increasingly interesting as potential drug targets for the treatment of a variety of central nervous system (CNS) disorders including epilepsy and chronic and acute neurodegeneration. In contrast to the ionotropic glutamate (iGlu) receptors of the N-methyl-D-aspartate (NMDA), 2-amino-3-[5-methyl-3-hydroxyisoxazol-4-yl]propionic acid (AMPA) and kainate types that form ion channels, mGlu receptors couple to G-proteins and modulate a variety of membrane enzymes and ion channels. The eight mGlu receptor subtypes revealed to date by molecular cloning exhibit not only distinct pharmacological properties, but also different functions in the brain. This article describes the potential disease targets of compounds acting at the various mGlu receptor subtypes, and the development of such compounds by reviewing both the primary and patent literature.

Abstract: The replicative cycle of the human immunodeficiency virus (HIV) offers a number of molecular targets for intervention by potential antiviral agents, yet the propensity of the virus to continuously mutate allows the organism to escape inhibition by anti-Hiv agents. This review summarises current knowledge on the therapeutic potential of newly identified molecular targets of the virus such as Vpr, Nef, antitat, cyclophilin A, p7 nudeocapsid protein, integrase, leucine zipper as well as the cellular targets, phosphatidic acid and kβ protein. Advances in new inhibitors of the established targets, reverse transcriptase (RT), protease (PR), Tat and Rev are also presented. Emphasis is placed on novel drugs currently in clinical trials, or those showing promise in pre-clinical development. Two sections covering the newly approved anti-AIDS drugs, 3TC™, saquinavir and stavudine and the merits of combination therapy as a powerful strategy to combat the virus are included, reflecting significant milestones achieved ...

Abstract: Commercially available glycopeptides Vancomycin (V) and Teicoplanin (T) are drugs of choice for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci (CNS), which are resistant to beta-lactams and almost all other first-line antibiotics. They are extensively used in the treatment of severe infections caused by multi-resistant Gram-positive pathogens including enterococci. Enterococcal infections have become a dramatic clinical problem since few antibacterial agents are efficacious against these refractory organisms and increasing resistance is rapidly eliminating the current options. The recent emergence and spread of resistance also to glycopeptides in VanA enterococci poses a serious threat for the future. Some strains of methicillin-resistant CNS have reduced susceptibility to T and occasionally to V. Currently, a major concern is the possibility already demonstrated at laboratory level, that high glycopeptide resistance could be transferred from enter...

Abstract: This review summarises the patent and primary literature relating to gene therapy for HIV infection over the last year and comments on treatments under pre-clinical evaluation or in Phase I and II clinical trials. There is relatively little activity as yet in the clinical trial arena and there have been few major innovations in gene therapy approaches over this period. Hanging over this field, as in other areas of gene therapy, is the controversy over patenting of ex vivo gene therapy and doubts regarding the utility of certain vectors such as adeno-associated virus (AAV).

Abstract: Squalene epoxidase inhibitors represent an attractive target for the control of sterol biosynthesis. Success in the search for fungal squalene epoxidase inhibitors has led to commercial availability of drugs from this class (e.g., terbinafine from Sandoz). The discovery of NB-598, a potent and selective mammalian squalene epoxidase inhibitor able to decrease serum low density lipoprotein-cholesterol levels in dogs, with a similar potency to simvastatin, has stimulated increased efforts towards the identification of new mammalian squalene epoxidase inhibitors. Such compounds represent an attractive alternative to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors as new therapeutic tools in the control of plasma low density lipoprotein-cholesterol levels, a major risk factor in coronary artery diseases. This article describes the recent development of this class of compounds, reviewing both the primary and patent literature.

Abstract: The bleomycins are a group of glycopeptide anticancer cytotoxic agents which have been used in the clinical treatment of several human malignancies as single or combination chemotherapy for over two decades. However, the risk of dose-dependent pulmonary toxicity, which ultimately results in pulmonary fibrosis, limits the scale of application. Meanwhile, the unique mechanism of the antitumour effects of bleomycins has also attracted considerable interest from biologists. Extensive studies at the molecular level have provided a guide to attempts to obviate the pulmonary toxicity. Recent progress made in the areas of drug delivery, electropermeabilisation and conjugate synthesis has provided valuable additional information to improve bleomycin chemotherapy. The patents and publications discussed in this review are selected from those covering the period from 1992 to date based on a Chemical Abstracts search.

Abstract: Immunosuppressive therapies to abrogate host reactivity to allografts have been applied since the early days of clinical transplantation. However, new immunosuppressive agents and treatment protocols are constantly evolving. Advances in our understanding of basic immune mechanisms have stimulated novel strategies for controlling graft rejection. T-cells play a central role in the specific immune response of allograft rejection, and strategies to prevent T-cell activation or effector function are thus potentially useful for immunosuppression. During the last few years numerous new immunosuppressive compounds have entered early and late phases of development for transplant immunomodulation. This review aims to define the field of antirejection drugs as it currently exists and to examine what the future holds by considering new compounds which have appeared recently in the patent literature.

Abstract: This review highlights current strategies and significant developments being employed in gene therapy for neoplastic diseases. Three main approaches, mutation compensation, molecular chemotherapy and genetic immunopotentiation, have been undertaken. Mutation compensation relies on strategies to ablate activated oncogenes at the level of DNA (triplex), messenger RNA (antisense or ribozyme) or protein (intracellular single chain antibodies), and augment tumour suppressor gene expression. Molecular chemotherapy uses the delivery of a toxin gene to tumour cells for eradication. This can be accomplished by either transductional targeting, whereby the toxin is specifically delivered to the tumour, or by transcriptional targeting, whereby tumour-specific transcriptional activators are employed selectively to ‘turn on’ the toxin gene exclusively within the tumour. Genetic immunopotentiation refers to treatment based on the induction of a specific immune response against tumour-associated antigens (TAAs). The main...

Abstract: The discovery of hepatitis C virus (HCV) in 1987 and the subsequent development of diagnostic tests has accounted for the majority of cases of viral hepatitis throughout the world. However, a significant number of cases cannot be assigned to any of the viral hepatitis groups (A - E). During 1995 two companies reported the identification of novel hepatitis viruses known as GBV-B and hepatitis G virus (HGV), which were found to be responsible for a large proportion of the remaining undiagnosed cases. Sequence analysis of these two viruses revealed them to be isolates of the same virus and, moreover, to be close homologues of HCV. The clinical significance of these new viruses is currently unclear, but preliminary epidemiologic evidence suggests they are often found as co-infections with HCV. The close similarity of these viruses to HCV and the fact that related viruses have also been identified which infect small primates, suggests that they may be useful as surrogate agents for the identification of novel ...

Abstract: Programmed cell death or apoptosis describes a process whereby cells actively commit to die. Under normal conditions, it is likely that apoptosis is required for embryogenesis, immune system function and tissue remodelling. Pathological conditions might lead to inappropriate inhibition or activation of apoptosis. The former is thought to occur in the development of cancers, while the latter might account for cellular degenerative disorders. Many central nervous system (CNS) disorders occur as a result of neurodegeneration but, while it is clear that cell death observed in these conditions is a result of both apoptosis and necrosis, it is not clear to what extent each contributes to the overiying pathology. If apoptosis plays a significant role in neuronal cell death there might be therapeutic potential in targeting the apoptotic mechanisms. This review discusses some of the more recent molecular mechanisms that might play a role in neuronal apoptosis. In addition, the in vitro and in vivo evidence for apo...

Abstract: Amgen is probably the most financially successful US biotechnology company. Its products are based upon recombinant versions of a number of important growth and differentiation factors including erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF). The importance of these products and the patenting strategy used by Amgen to protect its sales are discussed. From an analysis of Amgen's patents, it can be seen that a number of novel growth and differentiation factors are likely to be appearing on the market soon. These include a novel interferon megakaryocyte growth and development factor (MGDF), and the neurotrophic factors, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and keratinocyte growth factor (KGF). Of particular interest is the development of products related to the ob gene leptin, the rights of which have recently been acquired by Amgen.

Abstract: Multiple sclerosis (MS) is a form of chronic encephalomyelitis that results in demyelination of neuronal processes and subsequent neurological dysfunction. Demyelinated plaques are characterised by blood brain barrier compromise, infiltration of immune cells, and selective loss of myelin and oligodendrocyte function. Although there are genetic and environmental factors, autoimmunity is considered to be central to the pathogenesis of MS. Experimental allergic/autoimmune encephalomyelitis (EAE) is an excellent model of immune-mediated demyelination and has provided insight into the disease course of MS. Because EAE has a similar pathophysiology it has also been used as a testing ground for potential therapies of MS. Recent treatment strategies include modulation of antigen levels, prevention of T cell activation or function, modulation of cytokine activity, and promotion of oligodendrocyte regeneration and/or function. This review discusses the current experimental agents that have shown promise in the amel...