Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders.

Abstract

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.

• Authors: Satoshi Mikami, Shinji Nakamura, Tomoko Ashizawa, Izumi Nomura, Masanori Kawasaki, Shigekazu Sasaki, Hideyuki Oki, Hironori Kokubo, Isaac D Hoffman, Hua Zou, Noriko Uchiyama, Kosuke Nakashima, Naomi Kamiguchi, Haruka Imada, Noriko Suzuki, Hiroki Iwashita, Takahiko Taniguchi
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 60 Issue 18 Pg. 7677-7702 (09 28 2017) ISSN: 1520-4804 [Electronic] United States
• PMID: 28796496 (Publication Type: Journal Article)

Chemical References

• Phosphodiesterase Inhibitors
• Pyrazines
• Pyrazoles
• Pyrimidines
• pyrazolo(1,5-a)pyrimidine
• Cyclic Nucleotide Phosphodiesterases, Type 2
• PDE2A protein, human
• Cyclic GMP

Topics

• Animals
• Brain (drug effects, metabolism)
• Cognition (drug effects)
• Cognition Disorders (drug therapy, metabolism)
• Crystallography, X-Ray
• Cyclic GMP (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 2 (antagonists & inhibitors, chemistry, metabolism)
• Drug Design
• Halogenation
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred ICR
• Phosphodiesterase Inhibitors (chemistry, pharmacokinetics, pharmacology)
• Pyrazines (chemistry, pharmacokinetics, pharmacology)
• Pyrazoles (chemistry, pharmacokinetics, pharmacology)
• Pyrimidines (chemistry, pharmacokinetics, pharmacology)
• Rats
• Rats, Sprague-Dawley