PUBLICATION
Discovery of a Potent and Orally Bioavailable Hypoxia-Inducible Factor 2α (HIF-2α) Agonist and Its Synergistic Therapy with Prolyl Hydroxylase Inhibitors for the Treatment of Renal Anemia
- Authors
- Yu, Y., Yang, F., Yu, Q., Liu, S., Wu, C., Su, K., Yang, L., Bao, X., Li, Z., Li, X., Zhang, X.
- ID
- ZDB-PUB-211029-6
- Date
- 2021
- Source
- Journal of medicinal chemistry 64(23): 17384-17402 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Rats
- Animals
- Administration, Oral
- Prolyl-Hydroxylase Inhibitors/chemistry*
- Prolyl-Hydroxylase Inhibitors/pharmacology
- Prolyl-Hydroxylase Inhibitors/therapeutic use*
- Biological Availability
- Structure-Activity Relationship
- Anemia/drug therapy*
- Zebrafish
- Humans
- Renal Insufficiency, Chronic/drug therapy*
- Basic Helix-Loop-Helix Proteins/agonists*
- Drug Discovery*
- Rats, Sprague-Dawley
- Mice
- PubMed
- 34709043 Full text @ J. Med. Chem.
Citation
Yu, Y., Yang, F., Yu, Q., Liu, S., Wu, C., Su, K., Yang, L., Bao, X., Li, Z., Li, X., Zhang, X. (2021) Discovery of a Potent and Orally Bioavailable Hypoxia-Inducible Factor 2α (HIF-2α) Agonist and Its Synergistic Therapy with Prolyl Hydroxylase Inhibitors for the Treatment of Renal Anemia. Journal of medicinal chemistry. 64(23):17384-17402.
Abstract
Activation of hypoxia-inducible factor 2 (HIF-2) has emerged as a potent renal anemia treatment strategy. Here, the benzisothiazole derivative 26 was discovered as a novel HIF-2α agonist, which first demonstrated nanomolar activity (EC50 = 490 nM, Emax = 349.2%) in the luciferase reporter gene assay. Molecular dynamics simulations indicated that 26 could allosterically enhance HIF-2 dimerization. Furthermore, compound 26 had a good pharmacokinetic profile (the oral bioavailability in rats was 41.38%) and an in vivo safety profile (the LD50 in mice was greater than 708 mg·kg-1). In the in vivo efficacy assays, the combination of 26 and the prolyl hydroxylase inhibitor, AKB-6548, was confirmed for the first time to synergistically increase the plasma erythropoietin level in mice (from 260 to 2296 pg·mL-1) and alleviate zebrafish anemia induced by doxorubicin. These results provide new insights for HIF-2α agonists and the treatment of renal anemia.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping