Evaluation of 3-carbamoylpropanoic acid analogs as inhibitors of human hypoxia-inducible factor (HIF) prolyl hydroxylase domain enzymes

• Published in: Medicinal chemistry research Vol. 30; no. 4; pp. 977 - 986
• Main Authors: Chong, MuiPhin, Toh, LeeRoy, Tumber, Anthony, Chan, YanYing, Chan, MunChiang, Abboud, Martine I., Schofield, Christopher J., Yeoh, KarKheng
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.04.2021; Springer Nature B.V
• Subjects: Acids; Anemia; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Domains; Esters; Ethyl esters; Hydroxylase; Hypoxia; Hypoxia-inducible factor 1a; Inhibitors; Inorganic Chemistry; Medicinal Chemistry; Original Research; Pharmacology/Toxicology; Prolyl hydroxylase; Hypoxia-inducible factor; 3-carbamoylpropanoic acid derivatives; PHD inhibitors; HIF; Prolyl hydroxylase domain; 2-oxoglutarate/alpha-ketoglutarate dependent oxygenase
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-020-02681-7

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 IC 50 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.