Thursday, January 26, 2006

AstraZenaca makes inroads into future treatments of neurodegenerative disease

As discussed in our recent features World Neurodegeneratives Disease Markets, 2005-2009 and Neuroprotection - Drugs, Markets and Companies, treating neural degeneration associated with conditions such as Parkinson's Disease, Multiple Sclerosis and Alzheimer's Disease represents an $5-8 billion market. With the approval of new products, the neuroprotection market value will rise significantly over the next decade.

Stroke, one of the leading causes of death and adult disability worldwide, will also become an increasingly important indication for neuroprotective therapeutics as acute treatments for stroke continue to be limited in their utility (see Neuroprotection in Stroke)

One approach to neuroprotection involves the inhibition of JNK3. The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein (MAP) kinase family, which regulate signal transduction in response to environmental stress. Activation and nuclear localization of JNK3, a neuronal-specific isoform of JNK, has been associated with hypoxic and ischemic damage of CA1 neurons in the hippocampus. In particular, JNK3 has been found to have an upstream role in neuronal ischemic apoptosis implicating it in neural damage following ischemic stroke.

Whilst loss of either JNK1 or JNK2 alone appears to have no serious consequences, their combined knockout is embryonic lethal. In contrast, the loss of JNK3 is not embryonic lethal, but rather protects the adult brain from glutamate-induced excitotoxicity. Thus the development of selective JNK3 inhibitors represents a useful approach to limiting acute neural damage.

JNK3 has also been implicated in several chronic neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. JNK3 is highly expressed and activated in postmortem brains of individuals that suffered from Alzheimer's disease. Furthermore, mice that are deficient in JNK3 are more resistant to the development of disease in an animal model of Parkinson's disease than their wild-type littermates. The involvement of JNK3 in long-term neuronal diseases has therefore extended the potential of JNK3 inhibitors way past that of stroke.

In 1998, Vertex researchers solved the crystal structure of JNK3 and since then a number of companies have screened for selective JNK3 inhibitors. The most recent data to emerge has come from AstraZeneca and this is the subject of the Bioorg Med Chem Lett paper headlined in DailyUpdates (Jan 26th, 2005).

In this paper Swahn and colleagues from AstraZeneca report on the design and synthesis of a new series of JNK3 inhibitors. The rationally designed series was based on a combination of hits from high throughput screening and X-ray crystal structure information of compounds crystallized into the JNK3 ATP binding active site. This series displays selectivity against JNK1 and further development is eagerly awaited.


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