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-<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.
Authors
- David C. Gervasi
- Mark D. Sternlicht (ORCID: https://orcid.org/0000-0002-3644-3861)
- Demi R. S. Ng (ORCID: https://orcid.org/0000-0002-0348-2004)
- Michael D. Thompson (ORCID: https://orcid.org/0000-0003-3858-7516)
- Paramjeet Sidhu
- Savithri Ramurthy (ORCID: https://orcid.org/0000-0002-2444-5309)
- Ute Hoch (ORCID: https://orcid.org/0000-0001-7927-9830)
- Om Makwana
- Jack T. Lin
- Pierre Signore
- Grace Nelson (ORCID: https://orcid.org/0000-0001-6945-4842)
- Anthony D. Ho (ORCID: https://orcid.org/0000-0002-1656-0833)
- Ughetta del Balzo (ORCID: https://orcid.org/0000-0003-4102-6023)
- Dennis C. Koester (ORCID: https://orcid.org/0000-0003-2236-6372)
- Gail Walkinshaw
- Jenny Tsao
- Suzanne Spong
- Mohamed Abbas Ibrahim (ORCID: https://orcid.org/0000-0001-7535-5453)
- Xiaoqian Zhou
- Michael Barnes
- Mitchell C. Brenner
- Zhihua Wei
- Min Wu
- James Chou
- Elena Vaisberg
- Gerardo Pangilinan
Institutions
- FibroGen (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-06
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02889
- Citations
- 1
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- FibroGen