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

Takeshi Fukuda; Takeshi Kuribayashi; Rieko Takano; Koji Sasaki; Takashi Tsuji; Yoichi Niitsu; Ken Ishii; Masami Hashimoto; Daichi Baba; Shuichiro Ito; Naoki Tanaka

doi:10.1016/j.bmcl.2024.129799

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

Bioorg Med Chem Lett. 2024 May 15:108:129799. doi: 10.1016/j.bmcl.2024.129799. Online ahead of print.

Authors

Affiliations

¹ R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: fukuda.takeshi.zv@daiichisankyo.co.jp.
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.