title: Hypoxia-inducible factor stabilizers and other small-molecule erythropoiesis-stimulating agents in current and preventive doping analysis.
abstract: Increasing the blood's capacity for oxygen transport by erythropoiesis-stimulating agents (ESAs) constitutes a prohibited procedure of performance enhancement according to the World Anti-Doping Agency (WADA). The advent of orally bio-available small-molecule ESAs such as hypoxia-inducible factor (HIF) stabilizers in the development of novel anti-anaemia therapies expands the list of potential ESA doping techniques. Here, the erythropoiesis-stimulating properties and doping relevance of experimental HIF-stabilizers, such as cobaltous chloride, 3,4-dihydroxybenzoic acid or GSK360A, amongst others, are discussed. The stage of clinical trials is reviewed for the anti-anaemia drug candidates FG-2216, FG-4592, GSK1278863, AKB-6548, and BAY85-3934. Currently available methods and strategies for the determination of selected HIF stabilizers in sports drug testing are based on liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). For the support of further analytical assay development, patents claiming distinct compounds for the use in HIF-mediated therapies are evaluated and exemplary molecular structures of HIF stabilizers presented. Moreover, data concerning the erythropoiesis-enhancing effects of the GATA inhibitors K7174 and K11706 as well as the lipidic small-molecule ESA PBI-1402 are elucidated the context of doping analysis.
authors.affiliation: German Sport University Cologne, Cologne, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Beuck
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Schänzer
authors.forename: Mario
authors.initials: M
authors.lastname: Thevis
mesh_terms: D000740:Anemia / Q000188:drug therapy; D000818:Animals; D003035:Cobalt / Q000032:analysis / Q000494:pharmacology; D004300:Doping in Sports; D004920:Erythropoiesis / Q000187:drug effects; D050980:GATA Transcription Factors / Q000037:antagonists & inhibitors; D005998:Glycine / Q000031:analogs & derivatives / Q000032:analysis / Q000494:pharmacology; D006397:Hematinics / Q000032:analysis* / Q000494:pharmacology*; D006801:Humans; D062385:Hydroxybenzoates / Q000032:analysis / Q000494:pharmacology; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D015363:Quinolones / Q000032:analysis / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000032:analysis* / Q000494:pharmacology*; D015813:Substance Abuse Detection / Q000379:methods*
chemical_list: D050980:GATA Transcription Factors; D006397:Hematinics; D062385:Hydroxybenzoates; D051793:Hypoxia-Inducible Factor 1; C554359:N-((1-(cyclopropylethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl)carbonyl)glycine; D015363:Quinolones; D054852:Small Molecule Libraries; C009091:protocatechuic acid; D003035:Cobalt; C018021:cobaltous chloride; D005998:Glycine