Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor.
Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl)phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER)=6.2) despite the potent PDE10A inhibitory activity (IC50=0.94 nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER=1.4) and an excellent PDE10A inhibitory activity (IC50=0.080 nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3mg/kg by oral administration in mice.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: masato.yoshikawa@takeda.com.
Masato
M
Yoshikawa
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Haruhi
H
Kamisaki
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Jun
J
Kunitomo
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Hideyuki
H
Oki
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Hironori
H
Kokubo
CMC Center, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
Akihiro
A
Suzuki
CMC Center, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
Tomomi
T
Ikemoto
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Kosuke
K
Nakashima
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Naomi
N
Kamiguchi
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Akina
A
Harada
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Haruhide
H
Kimura
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Takahiko
T
Taniguchi
D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D006207:Half-Life; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009043:Motor Activity / Q000187:drug effects; D000078183:Oxindoles; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
C000609818:1-(cyclopropylmethyl)-4-fluoro-5-(5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one; D007211:Indoles; D000078183:Oxindoles; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; C022960:2-oxindole; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases
Inhibitors; P-gp-mediated efflux; Phosphodiesterase 10A (PDE10A); Schizophrenia