Corrigendum to “Tetrahydropyridin-4-ylpicolinoylglycines as novel and orally active prolyl hydroxylase 2 (PHD2) inhibitors for the treatment of renal anemia” [Eur. J. Med. Chem. 238 (2022) 114479]

作者: Zhang, Linjian ; Zhang, Xiaojin ; Sun, Zhuoli ; Li, Zhihong ; Fang, Shaocong ; Su, Kaijun ; Mao, Mingxuan

2023-07-13·Journal of Medicinal Chemistry1区 · 医学

Preferred Conformation-Guided Discovery of Potent and Orally Active HIF Prolyl Hydroxylase 2 Inhibitors for the Treatment of Anemia

1区 · 医学

Article

作者: Du, Zhongqiu ; Yang, Fulai ; Su, Kaijun ; Zhang, Xiaojin ; Sun, Zhuoli ; Chen, Yafen ; Zhang, Linjian ; Dong, Ying ; Li, Xiang ; Qiu, Xusheng ; Yang, Le ; Wu, Yue

In this work, we discovered a novel series of prolyl hydroxylase 2 (PHD2) inhibitors with improved metabolic properties based on a preferred conformation-guided drug design strategy. Piperidinyl-containing linkers with preferred metabolic stability were designed to match the dihedral angle of the desired docking conformation in the PHD2 binding site with the lowest energy conformation. Based on the piperidinyl-containing linkers, a series of PHD2 inhibitors with high PHD2 affinity and favorable druggability were obtained. Remarkably, compound 22, with an IC₅₀ of 22.53 nM toward PHD2, significantly stabilized hypoxia-inducible factor α (HIF-α) and upregulated the expression of erythropoietin (EPO). Furthermore, oral administration of 22 dose-dependently stimulated erythropoiesis in vivo. Preliminary preclinical studies showed that 22 has good pharmacokinetic properties and an excellent safety profile, even at 10 times the efficacious dose (200 mg/kg). Taken together, these results indicate that 22 is a promising candidate for anemia treatment.

2022-11-01·Annals of Translational Medicine

Hypoxia-inducible factor 1α enhances RANKL-induced osteoclast differentiation by upregulating the MAPK pathway

Article

作者: Gong, Yining ; Gao, Xiangcheng ; Qu, Zechao ; Feng, Mingzhe ; Huang, Wangli ; Kong, Lingbo ; Zhang, Bo ; Liu, Lin ; Wang, Yanjun ; Wang, Dong ; Yan, Liang

BackgroundHypoxia (low-oxygen tension) and excessive osteoclast activation are common conditions in many bone loss diseases, such as osteoporosis, rheumatoid arthritis (RA), and pathologic fractures. Hypoxia-inducible factor 1 alpha (HIF1α) regulates cellular responses to hypoxic conditions. However, it is not yet known how HIF1α directly affects osteoclast differentiation and activation. This study sought to. explore the effects of HIF1α on osteoclast differentiation and it's molecular mechanisms.MethodsL-mimosine, a prolyl hydroxylase (PHDs) domain inhibitor, was used to stabilize HIF1α in normoxia. In the presence of receptor activator of nuclear factor-kB (NF-kB) ligand (RANKL), RAW264.7 cells were cultured and stimulated by treatment with L-mimosine at several doses to maintain various levels of intracellular HIF1α. The multi-nucleated cells were assessed by a tartrate-resistant acid phosphatase (TRAP) and F-actin ring staining assays. The osteoclast-specific genes, such as Cathepsin K, β3-Integrin, TRAP, c-Fos, nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), and matrix metallo-proteinase 9 (MMP9), were analyzed by real time-polymerase chain reaction (RT-PCR). The expression of relevant proteins was analyzed by Western blot.ResultsL-mimosine increased the content of intracellular HIF1α in a dose-dependent manner, which in turn promoted RANKL-induced osteoclast formation and relevant protein expression by upregulating the mitogen-activated protein kinase (MAPK) pathways.ConclusionsOur findings suggest that HIF1α directly increases the osteoclast differentiation of RANKL-mediated RAW264.7 cells in vitro by upregulating the MAPK pathways.

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适应症	最高研发状态	国家/地区	公司	日期
炎症性肠病	临床3期	中国香港	InSilico Medicine, Inc.	2021-01-06
克罗恩病	临床前	中国	英矽智能(香港)有限公司初创企业	2022-01-30