2. Academic Validation
  3. Discovery of Novel 5-(Piperazine-1-carbonyl)pyridin-2(1 H)-one Derivatives as Orally eIF4A3-Selective Inhibitors

Discovery of Novel 5-(Piperazine-1-carbonyl)pyridin-2(1 H)-one Derivatives as Orally eIF4A3-Selective Inhibitors

  • ACS Med Chem Lett. 2017 Sep 8;8(10):1077-1082. doi: 10.1021/acsmedchemlett.7b00283.
Ryo Mizojiri 1,  Daisuke Nakata 1,  Yoshihiko Satoh 1,  Daisuke Morishita 1,  Sachio Shibata 1,  Misa Iwatani-Yoshihara 1,  Yohei Kosugi 1,  Mai Kosaka 1,  Junpei Takeda 1,  Shigekazu Sasaki 1,  Kazuaki Takami 1,  Koichiro Fukuda 1,  Masahiro Kamaura 1,  Shinobu Sasaki 1,  Ryosuke Arai 1,  Douglas R Cary 1,  Yasuhiro Imaeda 1
Affiliations

Affiliation

  • 1 Research, Takeda Pharmaceutical Company Ltd., Fujisawa, Kanagawa 251-8555, Japan.
PMID: 29057054 DOI: 10.1021/acsmedchemlett.7b00283
Abstract

Starting from our previous eIF4A3-selective inhibitor 1a, a novel series of (piperazine-1-carbonyl)pyridin-2(1H)-one derivatives was designed, synthesized, and evaluated for identification of orally bioavailable probe molecules. Compounds 1o and 1q showed improved physicochemical and ADMET profiles, while maintaining potent and subtype-selective eIF4A3 inhibitory potency. In accord with their promising PK profiles and results from initial in vivo PD studies, compounds 1o and 1q showed antitumor efficacy with T/C values of 54% and 29%, respectively, without severe body weight loss. Thus, our novel series of compounds represents promising probe molecules for the in vivo pharmacological study of selective eIF4A3 inhibition.

Keywords

Eukaryotic initiation factor 4A3 (eIF4A3) inhibitor; P-gp substrate; RNA helicase; metabolic stability; pyridin-2(1H)-one derivative; solubility.

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