Novel bone antiresorptive agents that selectively inhibit the osteoclast V-H+-ATPase

The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is a potential molecular target for the discovery of novel bone antiresorptive agents useful for the treatment of osteoporosis. In order to design novel compounds able to selectively inhibit the osteoclast V-ATPase we firstly identified the minimal structural requirements of bafilomycin A1, a macrolide antibiotic which potently inhibits all V-ATPases. This information allowed the design of 2-(indole)pentadienamide derivatives whose optimization led to a novel class of potent inhibitors that demonstrated a high degree of selectivity for the osteoclast V-ATPase. The most interesting derivative, SB-242784, was able to inhibit bone resorption by human osteoclasts in vitro and to completely prevent ovariectomy-induced bone loss in rats when administered orally at 10 mg kg(-1) day(-1). Structure activity relationships of this class of compounds were investigated further by replacing the 2,4-pentadienoyl chain with suitable spacers able to maintain the correct orientation and distance between the indole ring and the amide moiety.     

In vitro and in vivo antiresorptive effects of bisphosphonates in metastatic bone disease

Bone metastases commonly occur in the course of malignant tumor disease. For many years, attempts have been made to identify factors for the management of cancer-induced skeletal complications. Nowadays, synthetic antiresorptive agents are considered to be indispensable for the treatment of cancer-related skeletal events, such as bone metastasis. The most common of these drugs are the bisphosphonates, which represent one of the most significant advances over the last 10 years in the field of supportive care and cancer. They are used for the treatment of cancer-induced hypercalcemia, for the prevention and treatment of postmenopausal osteoporosis, for patients with bone metastases secondary to breast cancer and multiple myeloma. A third-generation bisphosphonate, zolendronate, has been shown to minimize the destructive consequences of bone metastases and to exert a profound effect on tumor-induced osteolysis and tumor growth in bone. Zoledronate is already used for the treatment of hypercalcemia of malignancy, multiple myeloma-related osteolytic events and for patients with documented bone metastases from solid tumors in conjunction with standard antineoplastic therapy. The structure-function activity of the three generations of bisphosphonates developed to date, the in vitro models used for studying their effects on osteoclasts and osteoblasts, as well as the results of clinical trials obtained by the third generation bisphosphonate, zoledronic acid, are presented.     

Novel approaches to fracture healing

The fractures that occur as a result of trauma frequently require multiple stage surgical procedures to achieve adequate union. Bone grafting with autogenous cancellous or cortico cancellous bone grafts is the traditional method used to repair bone defects. Most fractures will heal using this traditional procedure, however a number of fractures, up to 10% of the cases in United States alone, will result in delayed or impaired healing. Novel approaches are currently being investigated for the augmentation and acceleration of fracture healing. Some of these approaches include the use of biodegradable matrices; cell based approaches supplemented with osteogenic factors and genetic therapy. Cell based approaches for fracture healing have roused intense interest because of the great advance in the isolation and expansion of cells from the marrow that have the ability to differentiate into various types of cells including osteoblasts. In addition, the discovery and cloning of several proteins (bone morphogenetic proteins) that have the ability to induce bone formation, have contributed to the investigation of novel approaches to augment fracture healing. Use of genetic therapy for the augmentation of fracture healing has also recently gained strong interest. The attractive feature of gene therapy is that therapeutic proteins can be delivered locally to the fracture site in relatively high concentrations and in a sustained fashion. This review discusses these novel approaches and presents an assessment of their future clinical applicability.     

Novel approaches to antifungal prophylaxis

Antifungal prophylaxis represents a significant advance in the management of patients at risk from fungal infections in a variety of settings. Identification of patients at the highest risk and the utilisation of safe and effective drugs maximises the benefits of prophylaxis. Situations in which antifungal prophylaxis has been shown to be useful are bone marrow transplantation, liver and lung transplantation, surgical and neonatal intensive care units, secondary prophylaxis of fungal infections associated with HIV and neutropenia associated haematological malignancies and their treatment. New antifungal agents, such as the echinocandins and the new azoles, are available and have a potential role in antifungal prophylaxis. Future studies should evaluate which strategy is more useful; prophylaxis or pre-emptive therapy.     

Novel therapeutic approaches in IBS

Irritable bowel syndrome (IBS) remains an incompletely understood, common syndrome with significant unmet medical needs. Significant progress has been made in the development of novel therapies aimed at normalizing bowel habit alterations and abdominal discomfort, even though some of the most effective treatments are currently only available for patients under a restricted access program from the FDA. Preclinical evidence supports the potential usefulness of several compounds in development for the treatment of chronic abdominal pain. Recent new evidence for a possible role of altered microflora and altered host microbial interactions may provide new treatment targets in the future.     

Novel approaches to antifungal prophylaxis

Antifungal prophylaxis represents a significant advance in the management of patients at risk from fungal infections in a variety of settings. Identification of patients at the highest risk and the utilisation of safe and effective drugs maximises the benefits of prophylaxis. Situations in which antifungal prophylaxis has been shown to be useful are bone marrow transplantation, liver and lung transplantation, surgical and neonatal intensive care units, secondary prophylaxis of fungal infections associated with HIV and neutropenia associated haematological malignancies and their treatment. New antifungal agents, such as the echinocandins and the new azoles, are available and have a potential role in antifungal prophylaxis. Future studies should evaluate which strategy is more useful; prophylaxis or pre-emptive therapy.     

Novel approaches to fracture healing

The fractures that occur as a result of trauma frequently require multiple stage surgical procedures to achieve adequate union. Bone grafting with autogenous cancellous or cortico cancellous bone grafts is the traditional method used to repair bone defects. Most fractures will heal using this traditional procedure, however a number of fractures, up to 10% of the cases in United States alone, will result in delayed or impaired healing. Novel approaches are currently being investigated for the augmentation and acceleration of fracture healing. Some of these approaches include the use of biodegradable matrices; cell based approaches supplemented with osteogenic factors and genetic therapy. Cell based approaches for fracture healing have roused intense interest because of the great advance in the isolation and expansion of cells from the marrow that have the ability to differentiate into various types of cells including osteoblasts. In addition, the discovery and cloning of several proteins (bone morphogenetic proteins) that have the ability to induce bone formation, have contributed to the investigation of novel approaches to augment fracture healing. Use of genetic therapy for the augmentation of fracture healing has also recently gained strong interest. The attractive feature of gene therapy is that therapeutic proteins can be delivered locally to the fracture site in relatively high concentrations and in a sustained fashion. This review discusses these novel approaches and presents an assessment of their future clinical applicability.     

Novel therapeutic approaches in primary hyperoxaluria

ABSTRACT

Introduction: Currently, three types of primary hyperoxaluria (PH I–III) are known, all based on different gene-mutations affecting the glyoxylate metabolism in the liver. Disease hallmark is an increased endogenous oxalate production and thus massively elevated urinary excretion of oxalate and other type-specific metabolites. Hyperoxaluria induces the formation of calcium-oxalate kidney stones and/or nephrocalcinosis. In addition to that, a chronic inflammasome activation by hyperoxaluria per se, often leads to an early deterioration of kidney function, regularly resulting in end-stage renal disease (ESRD) at least in patients with type I PH. Except for vitamin B6 treatment in PH I, therapeutic regimen nowadays consists only of supportive measures, like significantly increased fluid intake and medication increasing the urinary solubility like alkaline citrate.

Areas covered: Disease burden can be severe, and both clinicians and scientist are eager in finding new therapeutic approaches. The currently ongoing clinical studies and promising research in this field are reported in this paper. To present a complete overview, we searched electronic databases, like Clinical trial gov, National Center for Biotechnology Information PubMed, congress reports, press releases and personal information acquired at congresses and conventions. Searches were conducted using the following medical headings: (primary) hyperoxaluria, PH, therapy, treatment and research.

Expert opinion: There is light on the horizon that new treatment options will be available in due time, as there are several promising therapeutic agents currently under investigation, some being at the first levels of drug development, but some already in ongoing clinical trials (phase I-III).     

Novel approaches to targeting neuropeptide systems

Generation and/or interruption of cell signalling by neuropeptides has been shown to be essentially, although not exclusively, mediated by one or several membrane-bound enzymes, giving rise to the concept of selective versus dual enzyme inhibitors. Because most of these enzymes are zinc metallopeptidases, novel inhibitors are now being designed based on the structure of these proteins. The physiological role of neuropeptides and their relationships with other peptide systems can be investigated by comparing results obtained using peptidase inhibitors and selective receptor antagonists with those obtained using mice in which genes encoding the various components of a peptide system have been deleted. The potential use of peptidase inhibitors, compared with exogenous agonists, as therapeutic agents (particularly as analgesics or antidepressants) and their use in the investigation of the neurobiology of drug abuse will be discussed with particular focus on enkephalins and cholecystokinin 8 (CCK-8).     

Novel approaches to inflammatory bowel disease

Ulcerative colitis and Crohn's disease, collectively known as inflammatory bowel disease (IBD), are chronic, spontaneously relapsing disorders of unknown cause. These diseases appear to be immunologically mediated and have genetic and environmental influences. Although the cause of these diseases remains obscure, the pathogenesis of chronic intestinal inflammation is becoming clearer, due to improved animal models of enterocolitis and important advances in immunological techniques. Traditional therapy for IBD, although helping to induce and maintain disease remission, does little to alter the underlying fundamental disease process. New IBD therapy has not developed significantly over the past twenty years and includes 5-aminosalicylic acid preparations, corticosteroids and immunomodulatory agents, such as azathioprine, 6-mercaptopurine and methotrexate. There is, therefore, a need for new, specific disease-modifying therapy and the development of such therapy has been hastened by a greater understanding of the pathophysiology of IBD. This review examines the most recent novel therapies for IBD, with specific emphasis on immunomodulatory and novel anti-inflammatory therapies. Recent clinical trials are reviewed, and the potential advances and clinical impact that these novel agents may provide are discussed.     

Novel approaches to treat muscular dystrophies

Muscular dystrophies (MD) are a clinically and genetically heterogeneous group of skeletal muscle-wasting diseases. Mutations in the dystrophin gene result in dystrophin deficiency, which constitutes the pathogenic basis of Duchenne and Becker MD (DMD and BMD). Several MD are caused by mutations in other recently identified genes coding for proteins linked to the sarcolemma, the nuclear envelope or the contractile apparatus. In addition, several MD have been mapped to different chromosomal loci and for most of them, the identification of the molecular defect is underway. The immediate result is an ongoing reclassification of the MD into disorders defined not by clinical characteristics but specific genetic mutations. At present, therapy of MD is based on symptomatic treatment and supportive care. Convincing evidence for clinical efficacy is only available for corticosteroids that also suffer from frequent and severe side effects. Up to now, curative therapy is not available, although promising new molecular therapies are under investigation in animal models of MD. Current treatment strategies are discussed and a perspective for effective molecular therapy is given.     

Novel approaches to target pancreatic cancer

Despite remarkable progress that has been made in the recent years in the treatment of gastrointestinal tumors, in particular colorectal cancer, the prognosis of pancreatic cancer remains dismal. Five years after diagnosis almost all patients have died. At early stages of the disease surgery is the only modality to achieve long term survival. In the palliative setting gemcitabine confers some benefit to patients with advanced pancreatic cancer. A large number of chemotherapy combinations has been tested in patients with advanced pancreatic cancer. Only one combination showed significant improvement of survival, however also increased toxicity. The introduction of targeted therapies raised hopes for a better treatment of pancreatic cancer. However, most of the compounds tested so far failed to improve the survival of patients with pancreatic cancer. This review summarizes molecular targets examined so far in pancreatic cancer including matrix metalloproteinase inhibitors, farnesyltransferase inhibitors, vascular endothelial growth factor and epidermal growth factor receptor inhibitors and points out novel promising strategies for this difficult-to-treat tumor.     

Novel approaches in antimalarial drug discovery

Introduction: The development of new antimalarial drugs remains of the utmost importance, since Plasmodium falciparum has developed resistance against nearly all chemotherapeutics in clinical use. In an effort to contain the resistance of P. falciparum against artemisinins and to further eradication efforts, studies are ongoing to identify novel and more efficacious approaches to develop antimalarials.

Areas covered: The authors review the classical and new approaches to antimalarial drug discovery, with a special emphasis on the various stages of the parasite's life cycle and the different Plasmodium species. The authors discuss the methodologies and strategies for early efficacy testing that aim to narrow down the portfolio of promising compounds.

Expert opinion: The increased efforts in the discovery and development of new antimalarial compounds have led to the recognition of new promising hits. However, there is still major roadblock of selecting the most promising compounds and then further testing them in early clinical trials, especially in the current restricted economy. Controlled human malaria infection has much potential for speeding-up the early development process of many drug candidates including those which target the pre-erythrocytic stages.     

Novel approaches to anticonvulsant drug discovery

Introduction: The history of epilepsy dates back to 2000 BC. Yet, it was not until 1912 that the activity of the first antiepileptic, phenobarbital was discovered by accident. After this discovery, the next antiepileptic drugs to be discovered (phenytoin and primidone) were based on the phenobarbital's structure. Then, in 1960, carbamazepine was developed empirically, while in 1962, valproate demonstrated anticonvulsant activity against experimental seizures. The next antiepileptic drugs synthesized were either modifications of the existing drugs (such as oxcarbazepine and pregabalin) or completely novel chemical structures (lacosamide, perampanel and retigabine).

Areas covered: The present paper briefly refers to the history of epilepsy and development of antiepileptic drugs. Further, the paper provides a discussion on the antiepileptogenic effects of antiepileptic drugs in terms of the constant percentage of epileptic patients with refractory seizures. The authors also review the likely factors involved in the false refractoriness (such as through the use of caffeine-containing beverages and smoking). Finally, the authors consider future directions in the search of novel antiepileptic drugs.

Expert opinion: In spite of the considerable number of newer antiepileptic drugs, the number of drug-resistant epileptic patients remains unchanged. This may be rather an indication of the suitability of the currently available discovery procedures for effective antiepileptic drugs in the whole population of epileptic patients. The authors, however, believe that it is likely that models of mimic chronic epilepsy will help bridge the gaps and aid in the discovery of novel antiepileptic drugs – ones that can effectively modify the course of the disease.     

Novel approaches for targeted cancer therapy

The clinical use of chemotherapeutic agents against malignant tumors is successful in many cases but suffers from major drawbacks. One drawback is lack of selectivity, which leads to severe side effects and limited efficacy; and another is the emergence/selection of drug-resistance. To limit non-specific toxicity and to improve the efficiency of cancer therapy, "tumor markers", which are proteins generally overexpressed on the surface of tumor cells, can be selectively targeted. Growth factor receptors are one of the most extensively studied tumor markers. The implication of growth factor receptors in the pathogenesis and evolution of cancer has clearly been established and therefore, provides a rationale for therapeutic intervention. The targeting of cytotoxic substances to tumor markers with "magic bullets" is an old idea that raised high expectations but also disappointment. Over the past decade, newly gained understanding of mechanisms for targeted therapy have brought new hopes. Pharmacological agents that selectively target and block the action of growth factors and their receptors have been attempted, such as monoclonal antibodies (mAbs) (whole molecule or fragments), bispecific antibodies, mAbs conjugated to drugs, toxins or radioisotopes, small peptidic and peptidomimetic molecules in free form or conjugated to drugs, anti-sense oligonucleotides, immunoliposomes-encapsulated drugs, and small molecule inhibitors. This review will focus on current developments of selective targeting and bypassing drug resistance in the management of growth factor receptor-overexpressing tumors.     

Novel approaches to antimalarial drug discovery

Major advances in our understanding of malaria parasite biology have been made. Coupled with the completion of the malaria genome, this has presented exciting opportunities for target-based antimalarial drug discovery. However, the unraveling of more validated biological targets will not necessarily translate into the identification of new chemical entities that are effective against drug resistant parasites in the long term. As history has already shown, development of antiplasmodial agents aimed at a single parasite target or specialized process has failed to stem the tide of drug resistance. This review highlights recent starting points and/or approaches to antimalarial drug discovery with particular emphasis on innovative efforts, which are not necessarily based on the identification of new drug targets and attendant inhibitor design. Approaches covered include utilization of validated chemical scaffolds, bioprecursor and carrier prodrugs, double drug development and/or multi-therapeutic strategies, use of metallocenic scaffolds, the medicinal chemistry of antimalarial natural products and in silico drug design.     

Novel approaches to flavivirus drug discovery

INTRODUCTION: The members of the family Flaviviridae, including West Nile virus, yellow fever virus and dengue virus, are important human pathogens that are expanding their impact around the globe. The four serotypes of dengue infect 50-100 million people each year, yet the only clinical treatment is supportive care to reduce symptoms. Drugs that employ novel inhibition mechanisms and targets are urgently needed to combat the growing incidence of dengue worldwide. AREAS COVERED: The authors discuss recently discovered flavivirus inhibitors with a focus on antivirals targeting non-enzymatic proteins of the dengue virus lifecycle. Specifically, the authors discuss the flaviviruses, the need for novel inhibitors and the criteria for successful antiviral drug development. Current literature describing new advances in antiviral therapy at each stage of the flavivirus lifecycle (entry, endosomal escape, viral RNA processing and replication, assembly and immune evasion) are evaluated and summarized. EXPERT OPINION: Overall, the prognosis of flavivirus antiviral drug development is positive: new effective compounds have been discovered and studied. However, repurposing existing compounds and a greater translation to the clinical setting are recommended in order to combat the growing threat of flaviviruses.     

Novel approaches to fight Streptococcus pneumoniae

Streptococcus pneumoniae affects millions of people worldwide. It is responsible for a wide spectrum of serious illnesses such as pneumonia, meningitis and bacteraemia. The highest rate of pneumococcal disease (and the highest mortality) occurs in young children, as well as in the elderly and the immunocompromised patients. Identification of S. pneumoniae in diagnostic procedures may significantly improve thanks to the descripion of new PCR-derived techniques. Vaccination based on the polysaccharidic capsule, together with benzylpenicillin-derived drugs, constitute the current choices to tackle pneumococcal diseases. However, the wide serotype diversity of S. pneumoniae and the emergence of antibiotic-resistant strains is fostering the development of new methods to fight this microorganism. In this sense, patents documenting the use of novel antibiotics of the fluoroquinolone or tetracycline families have recently been described. Moreover, surface-associated proteins are receiving an increasingly special attention, as they are synthesized by most pneumococcal strains and play an important role in virulence. New patented protein-based vaccines take into consideration these polypeptides. In this article we present the main relevant characteristics of this pathogen and review the most recent methods that have been patented for the prevention, diagnostic and treatment of the pneumococcal diseases.