Discovery of Novel 5‑(Piperazine-1-carbonyl)pyridin-2(1H)‑one Derivatives as Orally eIF4A3-Selective Inhibitors
Version 3 2017-09-25, 21:03
Version 2 2017-09-21, 20:18
Version 1 2017-09-13, 23:48
Posted on 2017-09-25 - 21:03
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.
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Mizojiri, Ryo; Nakata, Daisuke; Satoh, Yoshihiko; Morishita, Daisuke; Shibata, Sachio; Iwatani-Yoshihara, Misa; et al. (2017). Discovery of Novel 5‑(Piperazine-1-carbonyl)pyridin-2(1H)‑one Derivatives as Orally eIF4A3-Selective Inhibitors. ACS Publications. Collection. https://doi.org/10.1021/acsmedchemlett.7b00283
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AUTHORS (17)
RM
Ryo Mizojiri
DN
Daisuke Nakata
YS
Yoshihiko Satoh
DM
Daisuke Morishita
SS
Sachio Shibata
MI
Misa Iwatani-Yoshihara
YK
Yohei Kosugi
MK
Mai Kosaka
JT
Junpei Takeda
SS
Shigekazu Sasaki
KT
Kazuaki Takami
KF
Koichiro Fukuda
MK
Masahiro Kamaura
SS
Shinobu Sasaki
RA
Ryosuke Arai
DC
Douglas R. Cary
YI
Yasuhiro Imaeda