Discovery of 1‑[2-Fluoro-4-(1H‑pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl‑1H‑pyrazol-5-yl)pyridazin-4(1H)‑one (TAK-063), a Highly Potent, Selective, and Orally Active Phosphodiesterase 10A (PDE10A) Inhibitor

A novel series of pyridazinone-based phosphodiesterase 10A (PDE10A) inhibitors were synthesized. Our optimization efforts using structure-based drug design (SBDD) techniques on the basis of the X-ray crystal structure of PDE10A in complex with hit compound 1 (IC50 = 23 nM; 110-fold selectivity over...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2014-11, Vol.57 (22), p.9627-9643
Main Authors: Kunitomo, Jun, Yoshikawa, Masato, Fushimi, Makoto, Kawada, Akira, Quinn, John F, Oki, Hideyuki, Kokubo, Hironori, Kondo, Mitsuyo, Nakashima, Kosuke, Kamiguchi, Naomi, Suzuki, Kazunori, Kimura, Haruhide, Taniguchi, Takahiko
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Brain - drug effects
Crystallography, X-Ray
Cyclic GMP - metabolism
Drug Design
Humans
Inhibitory Concentration 50
Male
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Microsomes, Liver - drug effects
Movement - drug effects
Phencyclidine - chemistry
Phosphodiesterase Inhibitors - chemistry
Phosphoric Diester Hydrolases - chemistry
Protein Conformation
Pyrazoles - chemistry
Pyridazines - chemistry
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Summary:A novel series of pyridazinone-based phosphodiesterase 10A (PDE10A) inhibitors were synthesized. Our optimization efforts using structure-based drug design (SBDD) techniques on the basis of the X-ray crystal structure of PDE10A in complex with hit compound 1 (IC50 = 23 nM; 110-fold selectivity over other PDEs) led to the identification of 1-[2-fluoro-4-(1H-pyrazol-1-yl)­phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)­pyridazin-4­(1H)-one (27h). Compound 27h has potent inhibitory activity (IC50 = 0.30 nM), excellent selectivity (>15000-fold selectivity over other PDEs), and favorable pharmacokinetics, including high brain penetration, in mice. Oral administration of compound 27h to mice elevated striatal 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) levels at 0.3 mg/kg and showed potent suppression of phencyclidine (PCP)-induced hyperlocomotion at a minimum effective dose (MED) of 0.3 mg/kg. Compound 27h (TAK-063) is currently being evaluated in clinical trials for the treatment of schizophrenia.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm5013648