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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

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journal contribution
posted on 26.11.2014, 00:00 by Jun Kunitomo, Masato Yoshikawa, Makoto Fushimi, Akira Kawada, John F. Quinn, Hideyuki Oki, Hironori Kokubo, Mitsuyo Kondo, Kosuke Nakashima, Naomi Kamiguchi, Kazunori Suzuki, Haruhide Kimura, Takahiko Taniguchi
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.