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

Document Type

Article

Publication Date

4-1-2021

Abstract

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 mu M and 1.32 mu M, respectively. However, neither the acids nor their respective ethyl esters were observed to upregulate HIF-1 alpha levels in cells.

Keywords

Hypoxia-inducible factor, HIF, Prolyl hydroxylase domain, PHD inhibitors, 2-oxoglutarate, Alpha-ketoglutarate dependent oxygenase, 3-carbamoylpropanoic acid derivatives

Publication Title

Medicinal Chemistry Research

Divisions

fac_med

Funders

Universiti Sains Malaysia[1001.PKIMIA.811250],Bantuan Kecil Penyelidikan, University of Malaya[BKP004-2018],Wellcome Trust,Cancer Research UK

Volume

30

Issue

4

Publisher

Springer Verlag

Publisher Location

233 SPRING STREET, 6TH FLOOR, NEW YORK, NY 10013 USA

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