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TherapeuticAdvances: 4th October, 2002

Posted on: 11 Oct 02


This week we focus on new targets for asthma (MMP-9 & LXA4). We also identify emerging approaches to the unmet CNS diseases, Alzheimer's disease (Protein phosphatase 1) and stroke (ATII receptor antag
oct 4th is a company founded by industrial researchers for the drug development sector. Our panel of pharmaceutical scientists produces TherapeuticAdvances, a twice-monthly bulletin of cutting edge scientific research with therapeutic potential. Selected research is fully analyzed in DiscoveryDossiers. These dossiers can be produced for institutions to boost technology transfer/partnering activity. Alternatively, DiscoveryDossiers or third party PharmaReports can be purchased as overviews to support target identification, development or marketing efforts. Through CustomReports, companies can request LeadDiscovery to provide expert in-depth analyses of candidate drug discovery targets.


An overview of TherapeuticAdvances

4th October 2002

A free and unabridged version of TherapeuticAdvances is available at


This week's TherapeuticAdvances focuses on new targets for asthma, particularly MMP-9 and LXA4. We also identify emerging therapeutic approaches to unmet CNS diseases including Alzheimer's disease (Protein phosphatase 1) and stroke (angiotensin II receptor antagonists). Like angiotensin II, endothelin-1 is a classic cardiovascular target with expanding indications and "Focus on Metabolic Disease" highlights research implicating ETA receptors in the development of insulin resistance thus offering a new therapeutic target. Finally "Focus on Metastasis" centers on research into the relationship between tumor hypoxia and invasiveness.

In this weeks edition:

  • Advances in the treatment of asthma [more]
  • Stroke and Alzheimer's disease - target identification for unmet disease [more]
  • Endothelin-1 in the etiology insulin resistance [more]
  • Mechanisms of hypoxia-induced tumor invasiveness [more]


Advances in the treatment of asthma

Asthma is now thought to affect 155 million people worldwide. In the United States alone there has been a recent two-fold increase in the number of cases of asthma driving pharmaceutical market values up to as high as $8 billion worldwide. Despite a large number of drugs available to clinicians, up to 15% of patients suffer from uncontrollable disease symptoms, increasing the demand for novel therapies that possess new modes of action. LeadDiscovery's current "Target of the Month" is matrix metalloproteinase-9 (MMP-9). This enzyme is produced by normal alveolar macrophages and granulocytes and degrades extracellular matrix collagens and is implicated in a number of serious diseases such as stroke, atherosclerosis, cancer, arthritis, and recently COPD (see "Therapeutic and pharmaceutical approaches to COPD" - click here for access). More recently, MMP-9, levels of which are increased in asthmatic subjects, has been shown to be critical for the infiltration of inflammatory cells into the airways of antigen challenged mice. MMP-9 also plays a key role in the development of airway hyperresponsiveness in these mice. These data therefore support the targeting of MMP-9 in airway disease. A second emerging target for asthma that we highlight in this edition of TherapeuticAdvance is lipoxin (LX) A4, a leukocyte-derived eicosanoid that is generated during inflammation. Allergen challenged mice produce higher levels of airway LXA4 and over-express its receptor. Furthermore a LXA4 mimic blocked both airway hyper-responsiveness and pulmonary inflammation, while transgenic expression of human LXA4 receptors in murine leukocytes led to significant inhibition of pulmonary inflammation. These data along with earlier studies showing that LXA4 reduces airway obstruction in human asthmatics suggest that like MMP-9, targeting LXA4 may offer an advance in the treatment of asthma. [For further details of these and other projects log on to TherapeuticAdvances]

Stroke and Alzheimer's disease - target identification for unmet disease

Over the past decade, angiotensin II receptor antagonists have gradually been cutting into the anti-hypertensive market. More recently evidence has emerged implicating this therapeutic class in a range of other conditions. In a recent DiscoveryDossier, LeadDiscovery analyzed the role of AT(1) receptor antagonists as well as AT(4) receptor agonists in the treatment of anxiety and depression (for further details click here). TherapeuticAdvances now highlights the involvement of angiotensin receptors in the pathophysiology and potential treatment of stroke. AT(1) receptor stimulate neuronal regeneration by facillitating the activation of AT(2) receptors. Furthermore, blockade of brain and cerebrovascular AT(1) receptors by AT(1) receptor blockers prevents the reduction in blood flow, infarct development and neurological decline after brain ischemia. Stroke represents a major unmet market and current treatments center on the use of thrombolytics but only within a very narrow time frame. The identification of new targets such as angiotensin II receptor ligands thus holds considerable therapeutic potential.

A second major unmet CNS market, which like anxiety and depression, may be a target for angiotensin II receptor ligands is Alzheimer's disease (for further details click here). Four million Americans currently suffer from the condition and experts estimate that 22 million people around the world will be so afflicted by 2025. Until recently, researchers had almost no understanding of the disorder's causes or indeed the cognitive process, defects in which are a hallmark of Alzheimer's disease. Protein phosphatase 1 (PP1) has recently emerged as a candidate target for cognitive disorders. One isoform of the regulatory subunit of PP1, regulatory subunit 3, has recently been implicated through linkage studies to the development of Alzheimer's disease. Zurich-based researchers have now used a genetic model to demonstrate that PP1 promotes forgetfulness while inhibition of PP1 prolongs memory. This ground-breaking data is highlighted in "Focus on CNS Disease". [For further details of these and other projects log on to TherapeuticAdvances]

Endothelin-1 in the etiology insulin resistance

Like angiotensin II, Endothelin-1 is a classic cardiovascular target with expanding indications. This 21 amino acid peptide has vasoconstrictor, positive inotropic, mitogenic, and metabolic properties. In numerous disease states, including congestive heart failure, obesity, and diabetes, increased levels of ET-1 have been reported and are thought to be pathologically relevant. Previous clinical studies have demonstrated that ET-1 induces a state of insulin resistance and prevents insulin-stimulated glucose uptake by adipocytes through the activation of ETA receptors. More recently, researchers at Auburn University have demonstrated that ET-1 decreases basal and insulin-stimulated resistin secretion by 3T3 adipocytes suggesting that increases in ET-1 levels alter both the glucose handling properties and the endocrine function of adipocytes. These data and studies showing that ETA receptor antagonism markedly improves hyperglycemia and plasma glucose clearance in an animal model of diabetes supports the use of ETA receptor antagonists in the treatment of diabetes.

Mechanisms of hypoxia-induced tumor invasiveness

Preventing metastatic progression represents a major therapeutic challenge since once tumors invade distant organs cure is rarely achievable (see "Cancer Treatment 2002" for a full analysis of current and future pharmaceutical approaches to cancer). Tumor hypoxia is one factor that increases the ability of breast carcinoma cells to invade the extracellular matrix and is associated with a poor prognosis for breast cancer patients. Canadian-based researchers have now linked hypoxia and metastasis to nitric oxide (NO) signaling pathways and uPAR over-expression. This relationship was suggested to involve an endogenous and tonically active inhibition of uPAR expression by NO acting via protein kinase G. Hypoxia was shown to reduce NO signaling with a consequent increase in uPAR expression. These findings reveal that hypoxia-induced increases in tumor cell invasiveness (and possibly metastasis) requires inhibition of the nitric oxide signaling pathway and that selective activators of PKG may counter this process.

Please remember that you can learn more about the publications mentioned above by logging on to TherapeuticAdvances. This is completely free and without obligation, so why not click the link and pay us a visit. In addition please note that we are currently featuring 1 new reports:


  • The Next Generation Antifungals: Triazoles vs. Peptides [more]

New Service from LeadDiscovery: LeadDiscovery is currently producing between 25 and 50 DiscoveryDossiers each year. These full project analyses are designed to optimize preclinical decision making. If you require a full evaluation of the subject matter described in TherapeuticAdvances, or indeed any other therapeutic areas, but you do not want to wait for a DiscoveryDossiers to be produced, our CustomReport service may be of use [more]

Dr Jon Goldhill

Last updated on: 27/08/2010 11:40:18

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