{Reference Type}: Journal Article
{Title}: Discovery of DS-1093a: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia.
{Author}: Tanaka N;Fukuda T;Takano R;Sasaki K;Tsuji T;Goto R;Kuribayashi T;Yamaguchi K;Niitsu Y;Ishii K;Hashimoto M;Takahashi S;Obayashi H;
{Journal}: Bioorg Med Chem Lett
{Volume}: 111
{Issue}: 0
{Year}: 2024 Oct 1
{Factor}: 2.94
{DOI}: 10.1016/j.bmcl.2024.129891
{Abstract}: 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.