Phosphodiesterases (PDEs) are intracellular enzymes that hydrolyze cAMP and/or cGMP, and are involved in a diverse array of biological responses. Phosphodiesterase 2A (PDE2A) is highly expressed in the brain, such as the cortex, hippocampus, and striatum, regions associated with cognitive function and memory. This distribution pattern suggests that selective inhibition of PDE2A could increase cAMP and/or cGMP within these brain areas and, thereby, ameliorate the cognitive dysfunction seen in a range of neuropsychiatric and neurodegenerative disorders, including schizophrenia and Alzheimer's disease. High-throughput screening of our in-house compound library identified the hit compound with a PDE2A IC50 of 3800 nM. The ensuing ligand-based modifications led to the discovery of the promising lead with a PDE2A IC50 of 24 nM and 180-fold selectivity over all other PDE enzyme families. Further optimization of the lead compound was guided by its X-ray co-crystal structure in complex with PDE2A, culminating in the identification of the clinical candidate (TAK-915) as a highly potent, selective and brain-penetrating PDE2A inhibitor (IC50: 0.61 nM, PDE selectivity: 4100-fold). In this presentation, we highlight how through rational drug design using a co-crystal structure, we were ultimately able to identify the clinical candidate with the best balance of potency, selectivity and brain penetration.

Discovery of clinical candidate TAK-915, a highly potent, selective, and brain-penetrating phosphodiesterase 2A inhibitor for the treatment of cognitive disorders

255th National Meeting (2018)

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