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

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

Affiliation

  • 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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