Derivatives of the Clinically Used HIF Prolyl Hydroxylase Inhibitor Desidustat Are Efficient Inhibitors of Human γ‑Butyrobetaine Hydroxylase

The 2-oxoglutarate
(2OG)/Fe(II)-dependent γ-butyrobetaine
hydroxylase (BBOX) catalyzes the final step in l-carnitine
biosynthesis, i.e., stereoselective C-3 oxidation
of γ-butyrobetaine (GBB). BBOX inhibition is a validated clinical
strategy to modulate l-carnitine levels and to enhance cardiovascular
efficiency. Reported BBOX inhibitors, including the clinically used
cardioprotective agent Mildronate, manifest moderate inhibitory activity in vitro, limited selectivity, and/or unfavorable physicochemical
properties, indicating a need for improved BBOX inhibitors. We report
that the clinically used hypoxia-inducible factor-α prolyl residue
hydroxylase (PHD) inhibitors Desidustat, Enarodustat, and Vadadustat
efficiently inhibit isolated recombinant BBOX, suggesting that BBOX
inhibition by clinically used PHD inhibitors should be considered
as a possible off-target effect. Structure–activity relationship
studies on the Desidustat scaffold enabled development of potent BBOX
inhibitors that manifest high levels of selectivity for BBOX inhibition
over representative human 2OG oxygenases, including PHD2. The Desidustat
derivatives will help to enable investigations into the biological
roles of l-carnitine and the therapeutic potential of BBOX
inhibition.