%0 Journal Article
%T Discovery of DS-1093a: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia.
%A Tanaka N
%A Fukuda T
%A Takano R
%A Sasaki K
%A Tsuji T
%A Goto R
%A Kuribayashi T
%A Yamaguchi K
%A Niitsu Y
%A Ishii K
%A Hashimoto M
%A Takahashi S
%A Obayashi H
%J Bioorg Med Chem Lett
%V 111
%N 0
%D 2024 Oct 1
%M 39019240
%F 2.94
%R 10.1016/j.bmcl.2024.129891
%X Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We discovered DS44470011 in our previous study, which showed potent in vitro activity and in vivo efficacy based on HIF-PHD inhibition. However, DS44470011 was also found to exert genotoxic effects. By converting the biphenyl structure, which is suspected to be the cause of this genotoxicity, to a 1-phenylpiperidine structure, we were able to avoid genotoxicity and further improve the in vitro activity and in vivo efficacy. Furthermore, through the optimization of pyrimidine derivatives, we discovered DS-1093a, which has a wide safety margin with potent in vitro activity and an optimal pharmacokinetic profile. DS-1093a achieved an increase in hemoglobin levels in an adenine-induced rat model of chronic kidney disease after its continuous administration for 4 days.