HIF stabilizers

HIF (hypoxia-inducible factor) complex stabilizers are considered promising future drugs that could be used in conjunction with conventional treatments for anemia. Pharmaceutical companies aim to use them to develop alternatives to the current treatment of anemia with recombinant erythropoietin (rEPO).

The most advanced HIF complex stabilizer currently in development is roxadustat (FG-4592), a second-generation compound. The compound is currently undergoing various clinical trials and has not yet been approved as a drug. In contrast, the market launch of a first-generation compound, FG-2216, is no longer being pursued due to adverse effects that have occurred.
 

The advantage of using HIF complex stabilizers (low-molecular-weight compounds) compared to EPO preparations would be administration in tablet form, whereas EPO is typically injected subcutaneously.

Biochemistry and Physiology

HIF is a protein complex that is stabilized in the kidney when blood oxygen partial pressure is low and activates (upregulates) the EPO gene. This results in increased production of EPO, which in turn has a positive effect on erythrocyte formation and oxygen transport. Conversely
, when oxygen partial pressure is elevated, so-called prolyl hydroxylases—which degrade the HIF complex—become active, thereby inhibiting EPO synthesis.

Significance as a Doping Agent

Given the potential for improved oxygen transport via HIF complex stabilizers, a performance-enhancing effect comparable to EPO doping is expected for endurance athletes, meaning that misuse of these substances must be anticipated.
The first positive test results involving FG-4592 in sports were reported in 2015.

In 2017, the HIF stabilizer molidustat was detected for the first time.

Detection

As early as 2009, the first detection methods for HIF-complex stabilizers based on mass spectrometry were developed and introduced for doping controls.

Further publications

Thevis M , Schänzer W. Analytical approaches for the detection of emerging therapeutics and non-approved drugs in human doping controls. J Pharm Biomed Anal. 2014, 101:66-83
Abstract
 

Beuck S, Bornatsch W, Lagojda a, Schänzer W, Thevis M. Development of liquid chromatography-tandem mass spectrometry-based analytical assays for the determination of HIF stabilizers in preventive doping research Drug Testing and Analysis 2011, 3, 11-12: 756-770.
Abstract

Thevis M, Schänzer W Dopingmittel der Zukunft und deren Nachweis. Selektive Androgenrezeptor Modulatoren (SARMs) und HIF-Stabilisatoren F.I.T. Das Wissenschaftsmagazin, 1 (2009) 14 17  (article download)