Discovery of Novel, Potent, Orally Bioavailable and Efficacious, Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors for Hematopoietic Stem Cell Mobilization

  • J Med Chem. 2025 Mar 6. doi: 10.1021/acs.jmedchem.4c02889.
Min Wu  1 ,  Dennis C Koester  1 ,  Gail Walkinshaw  1 ,  Danny Ng  1 ,  Xiaoti Zhou  1 ,  Angel Ho  1 ,  Jenny Tsao  1 ,  Michael Barnes  1 ,  Mitchell C Brenner  1 ,  Suzanne Spong  1 ,  Grace Nelson  1 ,  David C Gervasi  1 ,  Elena Vaisberg  1 ,  Mark Sternlicht  1 ,  Parmjeet Sidhu  1 ,  Jack Lin  1 ,  Mohamed Ibrahim  1 ,  Michael D Thompson  1 ,  James Chou  1 ,  Gerardo Pangilinan  1 ,  Om Makwana  1 ,  Zhihua Wei  1 ,  Pierre E Signore  1 ,  Ughetta Del Balzo  1 ,  Ute Hoch  1 ,  Savithri Ramurthy  1
Affiliations
  • 1. FibroGen Inc., 409 Illinois Street, San Francisco, California 94154, United States.
PMID: 40047531 DOI: 10.1021/acs.jmedchem.4c02889
Abstract

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.

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