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 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.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Jun
J
Kunitomo
Masato
M
Yoshikawa
Makoto
M
Fushimi
Akira
A
Kawada
John F
JF
Quinn
Hideyuki
H
Oki
Hironori
H
Kokubo
Mitsuyo
M
Kondo
Kosuke
K
Nakashima
Naomi
N
Kamiguchi
Kazunori
K
Suzuki
Haruhide
H
Kimura
Takahiko
T
Taniguchi
D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000187:drug effects; D018360:Crystallography, X-Ray; D006152:Cyclic GMP / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects; D009068:Movement / Q000187:drug effects; D010622:Phencyclidine / Q000737:chemistry; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry*; D011487:Protein Conformation; D011720:Pyrazoles / Q000737:chemistry*; D011724:Pyridazines / Q000737:chemistry*
C000594749:1-(2-fluoro-4-(1H-pyrazol-1-yl)phenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; C119843:PDE10A protein, human; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP; D010622:Phencyclidine