Discovery and Synthetic Study of Balipodect, a Novel Phosphodiesterase 10A Inhibitor

Abstract

Phosphodiesterase 10A (PDE10A) inhibitors are expected as a novel treatment of schizophrenia with no or less adverse effects caused by typical and atypical antipsychotic drugs. In the pursue of developing a novel PDE10A inhibitor, a pyridazin-4(1H)-one derivative was identified as a hit compound by high throughput screening (HTS) and the X-ray co-crystal structure of the hit compound with PDE10A enabled us a rational structure-based drug design (SBDD) approach. Following optimization focusing on topological polar surface area (TPSA) to enhance the brain-penetration led to discovery of Balipodect, a highly potent, selective, and orally active PDE10A inhibitor (IC₅₀＝0.30 nM, 18,000-fold selectivity over other PDEs). Balipodect is being developed in clinical trials for the treatment of schizophrenia. This article describes the successful example of the structure- and property-based drug designs from the HTS hit to the clinical compound. The development of optimal synthetic routes depending on each stage of the drug discovery is also discussed.