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.
摘要：
抑制缺氧诱导因子脯氨酸酰羟化酶（HIF-PHD）代表了发现下一代肾性贫血治疗方法的有希望的策略。我们在之前的研究中发现了DS44470011,基于HIF-PHD抑制,其显示出有效的体外活性和体内功效。然而,还发现DS44470011发挥基因毒性作用。通过转化联苯结构，这被怀疑是这种遗传毒性的原因，1-苯基哌啶结构，我们能够避免遗传毒性，并进一步提高体外活性和体内功效。此外，通过优化嘧啶衍生物，我们发现了DS-1093a,具有广泛的安全范围，具有有效的体外活性和最佳的药代动力学特征。DS-1093a在连续给药4天后，在腺嘌呤诱导的慢性肾脏疾病大鼠模型中实现了血红蛋白水平的增加。
