Key result
Oral Compound 17 alleviates anemia in mice by stabilizing HIF-α and elevating EPO.
Why the study?
Does compound 17 alleviate anemia and demonstrate favorable pharmacokinetic and safety profiles in preclinical models?
Does compound 17 alleviate anemia and demonstrate favorable pharmacokinetic and safety profiles in preclinical models?
Compound 17 is a potent, orally bioavailable prolyl hydroxylase inhibitor that alleviates anemia in preclinical models and is advancing to phase I clinical trials.
Answers are grounded in this paper and cite their sources.
Supports advancement of compound 17 to phase I anemia trials; leaves open human efficacy, safety, and durability.
The design and discovery of a new series of (5-alkynyl-3-hydroxypicolinoyl)glycine inhibitors of prolyl hydroxylase (PHD) are described. These compounds showed potent in vitro inhibitory activity toward PHD2 in a fluorescence polarization-based assay. Remarkably, oral administration of 17, with an IC 50 of 64.2 nM toward PHD2, was found to stabilize HIF-α, elevate erythropoietin (EPO), and alleviate anemia in a cisplatin-induced anemia mouse model with an oral dose of 25 mg/kg. Rat and dog studies showed that 17 has good pharmacokinetic properties, with oral bioavailabilities of 55.7 and 54.0%, respectively, and shows excellent safety profiles even at a high dose of 200 mg/kg in these animals. Based on these results, 17 is currently being evaluated in a phase I clinical trial for anemia.
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Zhang et al. (2020) studied Anemia. Compound 17 ((5-(3-(4-Chlorophenoxy)prop-1-yn-1-yl)-3-hydroxypicolinoyl)glycine) was evaluated on in vitro inhibitory activity toward PHD2, HIF-α stabilization, EPO elevation, and anemia alleviation (IC 50 of 64.2 nM toward PHD2). Compound 17, an orally bioavailable prolyl hydroxylase inhibitor, stabilized HIF-α, elevated erythropoietin, and alleviated anemia in a mouse model, leading to its evaluation in a phase I trial.
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