Enarodustat Chemical Properties

Density 

1.44±0.1 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

DMSO:60.44(Max Conc. mg/mL);177.59(Max Conc. mM)
DMSO:PBS (pH 7.2) (1:4):0.2(Max Conc. mg/mL);0.59(Max Conc. mM)
DMF:30.0(Max Conc. mg/mL);88.15(Max Conc. mM)
Ethanol:25.0(Max Conc. mg/mL);73.46(Max Conc. mM)

form 

A solid

pka

0.58±0.53(Predicted)

color 

White to off-white

InChI

InChI=1S/C17H16N4O4/c22-13-8-12(7-6-11-4-2-1-3-5-11)21-16(19-10-20-21)15(13)17(25)18-9-14(23)24/h1-5,8,10,22H,6-7,9H2,(H,18,25)(H,23,24)

InChIKey

NALAUGMPMIVAOW-UHFFFAOYSA-N

SMILES

C(O)(=O)CNC(C1=C(O)C=C(CCC2=CC=CC=C2)N2N=CN=C12)=O

Enarodustat Usage And Synthesis

Uses

Enarodustat is in the process of being approved for use in treating anemia associated with chronic kidney disease.

Mechanism of action

Enarodustat(JTZ-951) inhibits HIF-PH and reduces the degradation of HIF-α, thereby increasing the production of endogenous erythropoietin (EPO) and improving anemia symptoms.

in vivo

Advantages

As an oral drug, Enarodustat offers the convenience of traditional injectable EPO stimulators and helps improve patient treatment compliance.

Synthesis

The dichloropyridine 62 was converted to the ester 64 by ortho-lithiation and subsequent carboxylate capture. Esterification was then carried out using the imine esterifying agent 63 under Lewis acid catalysis in 96% overall yield over two steps. Sequential SNAr reactions, first involving benzyl alcohol, then hydrazine hydrate, followed by treatment with trimethylol orthoesters under acidic conditions, afforded the triazole pyridine 65 in 63% yield over three steps. Addition of 65 to morpholine triggered a key Dimroth rearrangement, followed by regioselective iodination to afford the rearranged iodinated triazole 66 in 68% yield. Sonogashira coupling with phenylacetylene followed by removal of the tert-butyl group afforded the carboxylic acid 67 in 80% yield over two steps. Amide formation with glycine ethyl ester (68) followed by reduction of the acetylene and simultaneous removal of the benzyl protecting group liberated the phenolic hydroxyl group. Ester hydrolysis afforded enarodustat (X) as the free carboxylic acid in 67% overall yield over three steps.