"Emerging Drug Discovery Targets" provides a regular summary of some of the most exciting breaking information recently featured by the pharmaceutical analysts, LeadDiscovery. Information includes editorials on recently published journal articles, selected press releases and "intelligence reports". Our target audience includes business development personnel, senior management and researchers within the drug development sector as well as bioscience investors and analysts.

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In this weeks edition:

• Editorial comment on selected journal articles
  • Exploiting the peptide uptake transporters PEPT1 and PEPT2 to improve drug absorption and targeting [more]
  • The development of a dual 5-LO inhibitor/H1 receptor antagonist for the treatment of asthma [more]
  • Sitaxentan as an effective treatment of pulmonary arterial hypertension [more]
  • Kv1.3 potassium channel blockade as an approach to insulin resistance [more]
  • Drug delivery technology predicted to allow safer and more effective use of steroids in the treatment of rheumatoid arthritis [more]
  • Novartis’/Schering’s VEGF receptor tyrosine kinase inhibitor, PTK787/ZK222584 as a candidate treatment of rheumatoid arthritis [more]
• PharmaNews Bytes - June 2004
  • News from the American Diabetes Association's summer conference: Exenatide; LAF 237A; EXUBERA [more]
  • News from the American Society of Clinical Oncology: Statins as chemopreventative agents; changing attitudes to first line treatment of colorectal cancer [more]
  • Advances in the treatment of schizophrenia & bipolar disorder [more]
  • The development of novel HIV therapeutics [more]
• Today's breaking scientific publications for the drug development community [more]
  • Also available for the following therapeutic areas on subscription only
    • Oncology
    • Cardiovascular disease
    • Inflammation, Infectious diseases and Immunology
    • CNS disorders
    • Metabolic disorders

Exploiting the peptide uptake transporters PEPT1 and PEPT2 to improve drug absorption and targeting: Glucagon like Peptide-1 (GLP-1) is a gut hormone released after food consumption to stimulate insulin secretion. GLP-1 has a very short half-life due to its degradation by the proteolytic enzyme dipeptidyl peptidase-IV (DPP-IV; CD26) which cleaves peptides after proline residues. Therefore, specific inhibition of DPP-IV is an attractive therapeutic approach to stimulate glucose dependent insulin secretion. In addition to its role in glucose homeostasis, DPP-IV has been implicated in immune disorders, HIV-1 infection and tumor progression and hence indications for its inhibitors extend past the treatment of diabetes. One of the most advanced DPP-IV inhibitors is isoleucine thiazolidide (Ile-thiazolidide, P32/98) which was in phase II evaluation by Probiodrug. Researchers at the Technical University of Munich have recently shown that the oral activity of this drug results from its ability to bind at the intestinal PEPT1 transporter thereby allowing transport across the gut wall. This finding was exploited, using Ile-thiazolidide and its analogues to characterize assays able to quantify PEPT1 binding and transport. These tools open the way for the rational design of peptide linked drugs with improved intestinal absorption. A second similar protein PEPT2 transports peptides across the respiratory tract epithelium and another assay was developed for this transporter. This assay could allow the targeting of thiazolidides to the lung. The selective inhibition of DPP-IV within the airway may be of use in the treatment of lung cancer. More generally, harnessing peptide transporters to allow the improved uptake and targeting of therapeutics can be extended to many other drug classes and indications...[more on these findings]

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The development of a dual 5-LO inhibitor/H1 receptor antagonist for the treatment of asthma:  Numerous inflammatory mediators have been implicated in the etiology of asthma, many of which have been evaluated as therapeutic targets in LeadDiscovery's recent DiscoveryDossier "Asthma Therapeutics: New treatment options and emerging drug discovery targets". Blocking specific inflammatory mediators has frequently yielded unimpressive clinical results and instead the simultaneous targeting or more than one mediator may be of greater use. In our June edition of TherapeuticAdvances we highlight work by researchers at UCB who have developed a dual 5-LO inhibitor/H1 receptor antagonist...[more on these findings]

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Sitaxentan as an effective treatment of pulmonary arterial hypertension: Pulmonary arterial hypertension (PAH) represents an unmet market. Initial breakthroughs in treatment focussed on the rare form of this condition, idiopathic pulmonary arterial hypertension. Recently however a key advance in the treatment of PAH was made with the launch of Actelion's twice-daily Tracleer (bosentan) as the first orally active treatment of both idiopathic and secondary PAH. Tracleer is the first generation of a class of drugs known as endothelin receptor antagonists and blocks two distinct ET-1 receptor isoforms: ETA and ETB. The newer ETA receptor antagonist sitaxsentan sodium (Thelin TM) is approximately 6,500-fold more selective as an antagonist for the ETA receptors compared with the ETB receptors confering significant advanatges over less selective antagonists. The Sitaxsentan To Relieve Impaired Exercise (STRIDE-1) Trial was designed to evaluate the safety and efficacy of sitaxsentan in patients with symptomatic PAH. Results from this trial have recently been reported by Barst et al. in the American Journal of Respiratory & Critical Care Medicine and are discussed here...[more on these findings]

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Kv1.3 potassium channel blockade as an approach to insulin resistance: According to WHO, there are some 130 million diagnosed diabetics in the world, a figure that is predicted to increase to 300 million by 2025. The market for diabetes therapeutics is also rising with global sales reportedly topping $8.1 billion for the 12 months to September 2000, a 19% increase over the previous 12 months. Oral antidiabetic drugs are the leading class of drugs used to treat the disease and account for almost 63% of sales. The R&D activity surrounding novel oral treatments of diabetes is considerable and one particular target that has recently received attention is the Kv1.3 potassium channel. Blocking this channel has been thought to be of value in the treatment of multiple sclerosis and more recently for preventing weight gain. Now researchers from Yale have demonstrated that Kv1.3 channel blockers may also increase insulin sensitivity in genetically obese and diabetic mice...[more on these findings]

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Drug delivery technology predicted to allow safer and more effective use of steroids in the treatment of rheumatoid arthritis: An estimated 5 million individuals suffer from rheumatoid arthritis (for further information on the rheumatoid arthritis market click here). Corticosteroids are the most dramatically effective short-term anti-inflammatory drugs; however, clinical benefit for rheumatoid arthritis often diminishes with time. Because of their long-term systemic side effects, corticosteroids are usually given only after a careful and prolonged trial of less hazardous drugs. Liposomes are artificial vesicles efficiently phagocytosed by macrophages and recent advances such as the development of PEG-coated liposomes has increased their therapeutic utility. Researchers have now shown that a single intravenous treatment with prednisolone encapsulated in long-circulating PEG-liposomes produces strong and lasting resolution of joint inflammation in an animal model of rheumatoid arthritis. This important study demonstrates that liposomes target steroid to inflamed joints dramatically increasing efficacy suggesting that this technology could be employed to reduce the number of required steroid doses in the clinic and also associated adverse effects...[more on these findings]

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Novartis’/Schering’s VEGF receptor tyrosine kinase inhibitor, PTK787/ZK222584 as a candidate treatment of rheumatoid arthritis: As described above in the preceding section of this edition of Emmerging Drug Discovery Targets, rheumatoid arthritis is one of the more common autoimmune diseases. LeadDiscovery’s state of the art evaluation of rheumatoid arthritis therapeutics (click here) evaluates advances in our understanding of the etiology of the disease. One field of research extensively analyzed in this report is angiogenesis. Inhibitors of receptor tyrosine kinase with specific activity against the VEGFRs have been developed in an attempt to prevent angiogenesis. One such molecule is PTK787/ZK222584, synthesized and developed by Novartis Pharma AG and Schering AG. Having demonstrated activity in models of cancer, another indication for angiogenesis inhibitors, this molecule is currently in phase III trials for the treatment of various tumors. Now Novartis researchers have demonstrated the efficacy of PTK787/ZK222584 in animal models of rheumatoid arthritis...[more on these findings]

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Selected new reports:

• Management Reports on BioPortfolio by title 1-100
• Management Reports on BioPortfolio by title 101-200
• Management Reports on BioPortfolio by title 201-300
• Management Reports on BioPortfolio by title 301-400
• Management Reports on BioPortfolio by title 401-500
• Management Reports on BioPortfolio by title 501-600