Discovery of PDE2A inhibitors to treat memory deficits in mild cognitive impairment and Alzheimer's disease

Abstract Despite the fact that more than 50% of early stage of Alzheimer’s disease (AD) patients with mild cognitive impairment (MCI) will progress to dementia within 5 years, current therapies provide minimal symptomatic relief, without curing or halting disease progression. Phosphodiesterase-2A (PDE2A), the most prevalent of PDEs expressed in the cortex, hippocampus and amygdala, regions involved in cognitive impairment, has emerged as a promising target for the treatment of mild cognitive impairment without side effects. Despite promising preclinical data showing that some inhibitors of PDE2A inhibitors, such as Bay 60-7550 and ND 7001, enhance memory in animal models of AD, clinical studies have not advanced, due in part, to the low selectivity, poor metabolic stability and brain penetrance of available compounds. The broad, long-term goal of this project is to discover and develop novel inhibitors of PDE2A for the treatment of MCI. To streamline the exciting project toward a clinical candidate, we have assembled a team with expertise in medicinal chemistry and drug discovery and PDE-related pharmacology and pharmacokinetics. The complementary collaboration among FD Neurotechnologies (Dr. Fu Du), University at Buffalo (Drs. Ying Xu and James M. O’Donnell), and University of Arizona (Dr. Wei Wang) will synergize the effort by utilizing state-of-the-art drug discovery tools and techniques to discover and optimize novel and drug-like inhibitors of PDE2A and to evaluate their pharmacological effects in cell and animal models.Research Narratives The goal of this project is to discover and develop safe, highly selective, and brain-penetrant PDE2A inhibitors with superior memory enhancing efficacy and potential to advance into clinical development for the treatment of Alzheimer’s disease.