960539-70-2

Daprodustat is a novel HIF (Hypoxia inducible factor)-prolyl hydroxylase inhibitor.

daprodustat (gsk1278863) is a hif-prolyl hydroxylase inhibitor.hypoxia stimulates erythropoietin (epo) release through accumulation of hypoxia-inducible factor 1α (hif-1α), resulting in an increase of erythrocyte production by the bone marrow. hif-prolyl hydroxylase inhibitors have been used to selectively activate the phd-signaling pathway, leading to the stabilization of hifα subunits, which can affect the transcription of hif-responsive genes.

Daprodustat inhibits HIF-PH and reduces the degradation of HIF-α, thereby increasing the production of endogenous erythropoietin (EPO) and alleviating anemia symptoms.

Daprodustat can be prepared by the reaction of DCC (dicyclohexylcarbodiimide) and malonic acid (59). The cyclic urea 60 was generated with a yield of 72%. This step creatively used the classic coupling reagent DCC as a urea synthon and reacted in a modified Biginelli reaction. The cyclic urea 60 was placed under alkaline conditions and reacted in the presence of ethylisocyanoacetate to obtain the penultimate intermediate 61. The penultimate intermediate 61 was subjected to a saponification reaction to finally obtain daprodustat (IX) with a yield of 78%.

in-vitro biotransformation data indicated that gsk1278863 was primarily metabolized by cyp2c8 [1].

[1] hara k,takahashi n,wakamatsu a,caltabiano s. pharmacokinetics, pharmacodynamics and safety of single, oral doses of gsk1278863, a novel hif-prolyl hydroxylase inhibitor, in healthy japanese and caucasian subjects. drug metab pharmacokinet.2015 dec;30(6):410-8.
[2] brigandi ra,johnson b,oei c,et al. a novel hypoxia-inducible factor-prolyl hydroxylase inhibitor (gsk1278863) for anemia in ckd: a 28-day, phase 2a randomized trial. am j kidney dis.2016 jun;67(6):861-71.