Discovery of Novel, Potent, Orally Bioavailable and Efficacious, Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors for 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-N-(pyridazin-4-ylmethyl)-7,8-dihydro-2,7-naphthyridine-3-carboxamide 13, 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 13 to exhibit high PHD2 potency, improved solubility, and
an optimized PK profile. 13 was effective at enhancing
G-CSF-induced HSC mobilization in mice at a dose of 2 mg/kg.