Journal of Medicinal Chemistry p. 7677 - 7702 (2017)
Update date:2022-08-15
Topics:
Mikami, Satoshi
Nakamura, Shinji
Ashizawa, Tomoko
Nomura, Izumi
Kawasaki, Masanori
Sasaki, Shigekazu
Oki, Hideyuki
Kokubo, Hironori
Hoffman, Isaac D.
Zou, Hua
Uchiyama, Noriko
Nakashima, Kosuke
Kamiguchi, Naomi
Imada, Haruka
Suzuki, Noriko
Iwashita, Hiroki
Taniguchi, Takahiko
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. This article details the expedited optimization of our recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading to the discovery of clinical candidate 36 (TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. Successful identification of 36 was realized through application of structure-based drug design (SBDD) to further improve potency and PDE selectivity, coupled with prospective design focused on physicochemical properties to deliver brain penetration. Oral administration of 36 demonstrated significant elevation of 3′,5′-cyclic guanosine monophosphate (cGMP) levels in mouse brains and improved cognitive performance in a novel object recognition task in rats. Consequently, compound 36 was advanced into human clinical trials.
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