Evaluation of 3-carbamoylpropanoic acid analogs as inhibitors of human hypoxia-inducible factor (HIF) prolyl hydroxylase domain enzymes
Chong MP., Toh LR., Tumber A., Chan YY., Chan MC., Abboud MI., Schofield CJ., Yeoh KK.
There is current interest in developing human hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) inhibitors for the treatment of anemia and other hypoxia-related diseases. We describe the synthesis of 3-carbamoylpropanoic acid derivatives and their evaluation as human PHD-2 inhibitors. MS assays indicated that derivatives with a 3-carbamoylpropanoic acids-containing benzoxazole moiety are inhibitors of PHD-2 with IC50 values of 2.24 μM and 1.32 μM, respectively. However, neither the acids nor their respective ethyl esters were observed to upregulate HIF-1α levels in cells.