Prolyl hydroxylase domain-containing protein (PHD) inhibitors are useful as orally administered agents for the treatment of renal anemia. Based on the common structures of known PHD inhibitors, we found novel PHD inhibitor 1 with a 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid motif. The PHD2-inhibitory activity, lipophilicity (CLogP), and PK profiles (hepatocyte metabolism, protein binding, and/or elimination half-life) of this inhibitor were used as the evaluation index to optimize the structure and eventually discovered clinical candidate 42 as the suitable compound. Compound 42 was demonstrated to promote the production of erythropoietin (EPO) following oral administration in mice and rats. The predicted half-life of this compound in humans was 1.3–5.6 h, therefore, this drug may be expected to administer once daily with few adverse effects caused by excessive EPO production.

含脯氨酰羟化酶结构域的蛋白质（PHD）抑制剂可作为口服制剂治疗肾性贫血。基于已知的PHD抑制剂的常见结构，我们发现了具有2-[（（4-羟基-6-氧代-2,3-二氢-1 H-吡啶-5-羰基）氨基]乙酸基序的新型PHD抑制剂1。这种抑制剂的PHD2抑制活性，亲脂性（的CLogP）和PK分布（肝细胞代谢，蛋白结合，和/或消除半衰期）作为评价指标，以优化结构，并最终发现了临床候选42作为合适的化合物。化合物42已证明在小鼠和大鼠中口服给药后可促进促红细胞生成素（EPO）的产生。该化合物在人体中的预计半衰期为1.3-5.6小时，因此，该药物有望每天给药一次，而很少产生因过量EPO产生的不良反应。