PDE1A and PDE1B are highly expressed in neurons in brain regions involved in learning, memory and cognitive processing. PDE1 is an attractive target for the treatment of a number of psychiatric and neurological diseases, since it regulates the levels of cyclic nucleotides cAMP/cGMP, which are critical intracellular signaling molecules that regulate neuronal functions like synaptic plasticity, cognitive functions, neuronal survival, and axonal regeneration.<br/>Here we describe the discovery of the PDE1 inhibitor Lu AF64386 together with the SAR for the related class of quinazolines, including the X-ray structure of Lu AF64386 in complex with the catalytic domain of PDE1B. LU AF64386 is a highly permeable and brain penetrant PDE1 inhibitor with low intrinsic clearance and low propensity for Drug-Drug interactions. The relationship between exposure and PDE1 CNS occupancy was established by the use of a novel tritiated PDE1 ligand. The compound was able to elevate brain levels of cGMP and demonstrate pro-cognitive properties in doses corresponding to PDE1B CNS occupancy 30-60%. The compound has shown an overall profile making it attractive for further studies of PDE1 in vitro and in vivo.

Discovery of the brain penetrant Phosphodiesterase 1 (PDE1) inhibitor Lu AF64386

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.