2-{3-[4-(Alkylsulfinyl)phenyl]-1-benzofuran-5-yl}-5-methyl-1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-3beta with good brain permeability.
Glycogen synthase kinase 3beta (GSK-3beta) inhibition is expected to be a promising therapeutic approach for treating Alzheimer's disease. Previously we reported a series of 1,3,4-oxadiazole derivatives as potent and highly selective GSK-3beta inhibitors, however, the representative compounds 1a,b showed poor pharmacokinetic profiles. Efforts were made to address this issue by reducing molecular weight and lipophilicity, leading to the identification of oxadiazole derivatives containing a sulfinyl group, (S)-9b and (S)-9c. These compounds exhibited not only highly selective and potent inhibitory activity against GSK-3beta but also showed good pharmacokinetic profiles including favorable BBB penetration. In addition, (S)-9b and (S)-9c given orally to mice significantly inhibited cold water stress-induced tau hyperphosphorylation in mouse brain.
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 17-85 Jusohonmachi, 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan. Saitoh_Morihisa@takeda.co.jp
Morihisa
M
Saitoh
Jun
J
Kunitomo
Eiji
E
Kimura
Hiroki
H
Iwashita
Yumiko
Y
Uno
Tomohiro
T
Onishi
Noriko
N
Uchiyama
Tomohiro
T
Kawamoto
Toshimasa
T
Tanaka
Clifford D
CD
Mol
Douglas R
DR
Dougan
Garret P
GP
Textor
Gyorgy P
GP
Snell
Masayuki
M
Takizawa
Fumio
F
Itoh
Masakuni
M
Kori
D000818:Animals; D001921:Brain / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015195:Drug Design; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010069:Oxadiazoles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010539:Permeability; D047428:Protein Kinase Inhibitors / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D013237:Stereoisomerism; D013379:Substrate Specificity
D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3