Angiotensin as a target for the treatment of Alzheimer's disease, anxiety and depression

Mental disorders affect 44.3 million Americans in a given year. According to analysts the current global CNS therapeutics market is estimated at $40-55 billion, accounting for around 15% of the total global pharmaceuticals market. From a geographical perspective, the US accounts for about two-thirds of this revenue. Affective disorders (including depression) and anxiety are amongst the 10 leading causes of disability in the US and other developed countries, affecting 9.5% and 15% of the US population respectively. Antidepressants, which are also used for the treatment of anxiety, are largely limited to the modulation of monoamine activity and new therapeutic opportunities have displayed limited mechanistic diversity. Despite the development of newer antidepressants undesirable side effects remain a problem as does the slow onset of activity. Furthermore, approximately 30% of the population do not respond to current therapies. Thus, although the anti-depressant/anxiolytic market is, in general, mature there is considerable therapeutic and commercial potential attached to the development of new molecules with novel mechanisms of action. In contrast, Alzheimer's disease occupies a small share of the total CNS market but is currently experiencing massive growth. Most current therapies or molecules in advanced development for Alzheimer's disease compensate for altered neurotransmission and depend heavily on the inhibition of cholinesterase or the modulation of cholinergic receptors. More recent advances include the move towards targeting amyloid and molecules that reduce production, accumulation or toxicity of this molecule are likely to stand side by side with cholinergic modifying molecules in future strategies for the treatment of Alzheimer's disease.

Like the CNS market, drugs that have been launched for the treatment of hypertension are also massive revenue generators. Over the past decade, angiotensin II receptor antagonists have gradually been cutting into the market previously occupied by ACE inhibitors. Since the end of 2000, clinical trial data have been released suggesting that the angiotensin II receptor antagonists may have potential in a number of areas including diabetes and heart failure. As a result of the improved side-effect profile and expanded indications associated with the angiotensin II receptor antagonists this is the only class of antihypertensive compounds demonstrating significant growth. Current global sales are around $2 million and continue to increase by about 35% per year (based on sales figures from 1998-2001). Identification of additional indications is appealing since this will further boost sales.

A body of data has been accumulating offering evidence that angiotensin receptor ligands may be of use in the treatment of depression, anxiety and cognitive disorders including Alzheimer's. Hence this class of molecule may bridge the two massive fields of CNS and cardiovascular disorders. LeadDiscovery in collaboration with Dr Paul Gard, global field leader in CNS actions of angiotensin ligands, has produced a dossier analyzing potential new indications for angiotensin II receptor antagonists. This report should allow companies previously involved in the development of this class as an approach to hypertension to significantly increase revenue potential. This report therefore overviews the clinical characteristics and current treatment options of the major CNS disorders for the benefit of cardiovascular disease experts. On the other hand this report also offers researchers in the field of CNS disorders the opportunity to assess the benefits of testing existing or future angiotensin receptor antagonists for antidepressant/anxiolytic or memory enhancing activity. Hence we offer a background to the angiotensin system for those with a focus on CNS disorders. A major part of this report describes in detail the evidence supporting an involvement of this system in the treatment of depression, anxiety and cognitive disorders including Alzheimer's disease. We conclude that angiotensin II type 1 receptor antagonist may be able to treat each of these disorders. Furthermore, agonists of the angiotensin type 4 receptor may be able to further stimulate cognitive function in Alzheimer's disease patients.

Having established a proof of concept for using angiotensin receptor ligands for the treatment of CNS disorders, we then analyze the market and pharmaceutical activity surrounding these conditions. We identify those molecules on the market and in development for the treatment of depression, anxiety and Alzheimer's disease classifying each by pharmacological mode of action and by level of development. This shows that most molecules in development or on the market are limited to the modulation of monoamine activity. Through our trend analysis we identify which pharmacological classes are receiving growing attention and which are receiving decreasing interest. The results of these analyses support the claim that molecules with novel modes of action are currently in the spotlight. Likewise we identify angiotensin receptor ligands in development and classify them according to indication and level of development. This, and trend analysis clearly shows the level of maturity that angiotensin type 1 and type 2 receptor antagonists have reached. We profile each of these molecules and show the limited indications for angiotensin receptor ligands therefore supporting the conclusion that the revenue generated this class could be dramatically boosted by expanding indication to include CNS disorders. We further show that the level of pharmaceutical activity surrounding angiotensin type 4 receptors is virtually non-existent, thereby offering additional opportunities. Moreover our analysis of patent activity suggests that little early stage research is currently being reported with respect to both type 4 receptor agonists or CNS indications of type 1 antagonists.

Because the angiotensin system has the potential to span the two diverse therapeutic areas of CNS and cardiovascular disorders there is considerable scope for industrial collaboration. Companies with expertise in hypertension may wish to collaborate with those that have previously focussed on the CNS. Thus we identify companies involved in both area and further identify those companies with a history of co-development/in-licensing so as to encourage collaboration.

Although there is significant scope for broadening the indications of existing angiotensin receptor antagonist to include CNS disorders the possible benefits of further early stage development are also clear. For example companies with large libraries of angiotensin-related molecules may consider screening or molecular modelling approaches to identify those compounds more suited for treating depression, anxiety and Alzheimer's disease. Such molecules may be characterized by improved CNS penetration or they may have additional angiotensin type 4 receptor agonist activity. This reports therefore concludes by suggesting screening architectures that companies may wish to use to develop this most interesting, novel and potentially lucrative corner of the angiotensin system.