R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Bioorg Med Chem Lett. 2024 Aug 1;108:129799. doi: 10.1016/j.bmcl.2024.129799. Epub 2024 May 15.
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.
抑制缺氧诱导因子脯氨酰羟化酶（HIF-PHD）代表了发现治疗肾性贫血的下一代疗法的有前途的策略。我们基于使用 HIF-PHD2 与化合物的晶体结构进行的 FG-2216 的支架跳跃，确定了具有 HIF-PHD 抑制活性的嘧啶核心。通过优化嘧啶核心的 2-和 6-位的取代基，我们发现了 DS44470011，它提高了细胞中促红细胞生成素（EPO）释放的效果。DS44470011 口服给予食蟹猴增加了血浆 EPO 水平。
