Discovery of DS44470011: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia.
Bioorg Med Chem Lett
; 108: 129799, 2024 Aug 01.
Article
de En
| MEDLINE
| ID: mdl-38754564
ABSTRACT
Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Hypoxia-inducible factor-proline dioxygenases
/
Inhibiteurs de prolyle hydroxylases
/
Anémie
/
Macaca fascicularis
Limites:
Animals
/
Humans
Langue:
En
Journal:
Bioorg Med Chem Lett
Sujet du journal:
BIOQUIMICA
/
QUIMICA
Année:
2024
Type de document:
Article
Pays de publication:
Royaume-Uni