2. Academic Validation
  3. Discovery of DS-1093a: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia

Discovery of DS-1093a: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia

  • Bioorg Med Chem Lett. 2024 Jul 15:111:129891. doi: 10.1016/j.bmcl.2024.129891.
Naoki Tanaka 1,  Takeshi Fukuda 2,  Rieko Takano 2,  Koji Sasaki 2,  Takashi Tsuji 2,  Riki Goto 2,  Takeshi Kuribayashi 2,  Kyoji Yamaguchi 2,  Yoichi Niitsu 2,  Ken Ishii 2,  Masami Hashimoto 2,  Shinichi Takahashi 2,  Hisakuni Obayashi 2
Affiliations

Affiliations

  • 1 R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: tanaka.naoki.ri@daiichisankyo.co.jp.
  • 2 R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 39019240 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.

Keywords

DS-1093a; Erythropoietin (EPO); Hemoglobin (Hgb); Hypoxia-inducible factor prolyl hydroxylase (HIF-PHD); Renal anemia.

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