2-(2-Phenylmorpholin-4-yl)pyrimidin-4(3H)-ones; a new class of potent, selective and orally active glycogen synthase kinase-3β inhibitors

  • Bioorg Med Chem Lett. 2013 Dec 15;23(24):6933-7. doi: 10.1016/j.bmcl.2013.09.020.
Kenji Fukunaga  1 ,  Fumiaki Uehara ,  Keiichi Aritomo ,  Aya Shoda ,  Shinsuke Hiki ,  Masahiro Okuyama ,  Yoshihiro Usui ,  Kazutoshi Watanabe ,  Koichi Yamakoshi ,  Toshiyuki Kohara ,  Tokushi Hanano ,  Hiroshi Tanaka ,  Susumu Tsuchiya ,  Shinji Sunada ,  Ken-Ichi Saito ,  Jun-ichi Eguchi ,  Satoshi Yuki ,  Shoichi Asano ,  Shinji Tanaka ,  Akiko Mori ,  Keiji Yamagami ,  Hiroshi Baba ,  Takashi Horikawa ,  Masatake Fujimura
Affiliations
  • 1. Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
PMID: 24176395 DOI: 10.1016/j.bmcl.2013.09.020
Abstract

A series of 2-(2-phenylmorpholin-4-yl)pyrimidin-4(3H)-ones was synthesized and examined for their inhibitory activity against glycogen synthase kinase-3β (GSK-3β). We found 21, 29 and 30 to possess potent in vitro GSK-3β inhibitory activity with good in vitro PK profiles. 21 demonstrated significant decrease of tau phosphorylation after oral administration in mice and excellent PK profiles.

Keywords
Alzheimer’s disease; Glycogen synthase kinase-3β; Hyperphosphorylation; Tau protein.
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