2021 Volume 79 Issue 6 Pages 581-591
Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer’s disease through upregulation of cyclic nucleotides in the brain and thereby achieve potentiation of cyclic nucleotide signaling pathways. In the search for a potent, selective, in vivo active PDE2A inhibitor, pyrazolo［1,5-a］pyrimidine 2 was identified as a hit compound from high-throughput screening (HTS) campaign of our in-house compound library. The ligand-based lead generation efforts led to the discovery of the promising lead molecule 8a. Further optimization of this lead was guided by its X-ray co-crystal structure in complex with PDE2A, thus culminating in the identification of the clinical candidate (1, TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. This article details the expedited lead generation and ensuing optimization approaches leading to the discovery of clinical candidate, as well as the synthetic route of TAK-915 for 1-week toxicological studies.
