Over the past decade, angiotensin II receptor antagonists have gradually been cutting into the market previously occupied by ACE inhibitors, and indeed the former 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 for angiotensin II receptor antagonists is appealing since this will further boost sales. The implication of angiotensin II AT(1) receptor antagonists and AT(4) receptor agonists in the massive CNS arena as recently highlighted by LeadDiscovery, specifically with respect to the treatment of anxiety, depression and Alzheimer's disease is therefore of interest. TherapeuticAdvances now highlights the involvement of angiotensin receptors in the pathophysiology and potential treatment of stroke. In animal models, inhibition of the brain renin angiotensin system has proved to be beneficial with respect to stroke incidence and outcome. AT(1) receptor antagonists enable endogenous angiotensin II to stimulate neuronal regeneration via activation of AT(2) receptors. Furthermore, blockade of brain and cerebrovascular AT(1) receptors by AT(1) receptor blockers also prevents the reduction in blood flow during brain ischemia, reduces the volume of ischemic injury and improves neurological outcome after brain ischemia. Together these data suggest that AT(1) receptor antagonists may be of use in reducing ischemia and also the neural damage caused by hypoxia during stroke. Perhaps the most persuasive evidence to support this conclusion is a recent analysis of data obtained from the heart outcomes prevention evaluation (HOPE) study. This analysis reveals that an ACE inhibitor reduces the incidence of ischemic stroke and also improves the cognitive and functional outcome in patients who suffered a stroke. Similar studies focusing on AT(1) receptor antagonists are eagerly awaited. Ischemic stroke affects about 600,000 Americans each year, 8% of whom die within 30 days. A further 15-30% are permanently disabled and 20% require institutional care. Direct and indirect costs of stroke are therefore immense. The treatment of ischemic stroke remains one of the most challenging areas of medicine today. At present, only thrombolysis is approved as a treatment strategy, and for only a brief window of time. Since many patients present far beyond this three-hour window, not surprisingly most patients receive only palliative care. In order to open the window of therapeutic opportunity, the pharmaceutical industry is currently focusing on the development of new opportunities and targeting angiotensin may offer one strategy.

Entry date October, 2002

Adapted from Culman et al, J Hum Hypertens 2002 Aug;16 Suppl 3:S64-70

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