Discovery of DS44470011: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia

  • Bioorg Med Chem Lett. 2024 Aug 1:108:129799. doi: 10.1016/j.bmcl.2024.129799.
Takeshi Fukuda  1 ,  Takeshi Kuribayashi  2 ,  Rieko Takano  2 ,  Koji Sasaki  2 ,  Takashi Tsuji  2 ,  Yoichi Niitsu  2 ,  Ken Ishii  2 ,  Masami Hashimoto  2 ,  Daichi Baba  2 ,  Shuichiro Ito  2 ,  Naoki Tanaka  2
Affiliations
  • 1. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
  • 2. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 38754564 DOI: 10.1016/j.bmcl.2024.129799
Abstract

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels.

Keywords
Erythropoietin (EPO); Hypoxia-inducible factor (HIF); Hypoxia-inducible factor prolyl hydroxylase (HIF-PHD); Renal anemia.
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