Alzheimer's disease (AD), a neurodegenerative disease, is a leading cause of dementia in elderly. Currently about 5.4 million Americans (1 in 8 persons 65 or older) are living with AD, and the number is expected to triple by the year 2050. Approximately $200 billion per year is spent on all aspects of caring for AD patients, yet there is no therapy available to block the inevitable cognitive decline from the disease. The small molecule drugs that have been developed based on amyloid cascade hypothesis and COX-2 inhibition have not shown a clear clinical benefit so far. Thus it would be very important to focus on identification of novel drug targets and small molecules that work through novel mode of biological action for future AD therapy.

Prostanoid EP2 receptor is emerging as a novel biological target promoting inflammation and subsequent neuropathology in variety of neurodegenerative disease models including AD. In vitro and in vivo studies from EP2 knockout models have shown that chronic activation of EP2 in AD brain exacerbates disease pathology. However, no tests have been done by pharmacological inhibition of this receptor to confirm that EP2 receptor is a druggable target, in part, due to lack of available EP2 antagonists until recently. We have now developed selective small molecule antagonists for this receptor, and like to test them in vivo to demonstrate EP2 antagonism will block the progression of the disease in 5XFAD mouse model of AD.