1000025-07-9

Vadadustat is an inhibitor of hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PH2) and HIF-PH3 (IC₅₀s = 1.1 and 0.39 micromolar, respectively). It stabilizes HIF-1α in mouse hepatocyte nuclear extracts. Vadadustat (50 and 100 mg/kg) increases erythropoietin levels in mouse serum.

Vadadustat is a novel HIF (Hypoxia-inducible factor) stabilizer. It provides an effective anemia treatment in nondialysis-dependent chronic kidney disease.

Vadadustat is used to treat anemia in dialysis-dependent and non-dialysis-dependent chronic kidney disease patients.

Vadadustat inhibits PDH and reduces the degradation of HIF-α, thereby increasing the production of endogenous erythropoietin (EPO) and improving anemia symptoms.

Boronic acid 69 and pyridine nitrile 70 were coupled via Suzuki coupling to give biphenyl 71. Crystallization of 71 was required to remove small amounts of undesired regioisomer coupling products. One-pot reaction: aromatic substitution with methoxy anion. Hydrolysis of the nitrile was performed simultaneously. These two independent operations were performed in one pot to give compound 72 in 92% overall yield for the two steps. Carboxylic acid 72 and amine 73 were amidated using CDI (carbodiimide) as coupling agent to give compound 74. Aluminum-mediated demethylation of 74 removed the ester and ether functionalities to give vadadustat (XI) in 84% yield.

Vadadustat offers the convenience of traditional injectable EPO stimulators, helping to improve patient compliance with treatment. In clinical trials, Vadadustat has been shown to improve hemoglobin levels in CKD patients and has good safety and tolerability.

[1] ROBERT LABES  Kameliya R. Prolyl hydroxylase inhibitors, polydrug use, and the phosphoproteome[J]. Acta Physiologica, 2022, 237 1. DOI: 10.1111/apha.13898