Discovery ofNovel, Potent, Orally Bioavailable andEfficacious, Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitorsfor Hematopoietic Stem Cell Mobilization

Hematopoietic stem cell (HSC) mobilization is often difficult to achieve in patients suffering from multiple myeloma and non-Hodgkin’s lymphoma. Granulocyte-colony stimulating factor (G-CSF) therapy alone has often not led to the desired outcomes. Herein, we describe the discovery of 7-cyclohexyl-4-hydroxy-8-oxo-<i>N</i>-(pyridazin-4-ylmethyl)-7,8-dihydro-2,7-naphthyridine-3-carboxamide <b>13</b>, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, which was discovered by focusing on drug-like properties. Building on a previous discovery that HIF-PH inhibitors can enhance HSC mobilization in combination with G-CSF, we optimized <b>13</b> to exhibit high PHD2 potency, improved solubility, and an optimized PK profile. <b>13</b> was effective at enhancing G-CSF-induced HSC mobilization in mice at a dose of 2 mg/kg.