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2.
J Med Chem ; 66(13): 8545-8563, 2023 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-37367818

RESUMEN

In this work, we discovered a novel series of prolyl hydroxylase 2 (PHD2) inhibitors with improved metabolic properties based on a preferred conformation-guided drug design strategy. Piperidinyl-containing linkers with preferred metabolic stability were designed to match the dihedral angle of the desired docking conformation in the PHD2 binding site with the lowest energy conformation. Based on the piperidinyl-containing linkers, a series of PHD2 inhibitors with high PHD2 affinity and favorable druggability were obtained. Remarkably, compound 22, with an IC50 of 22.53 nM toward PHD2, significantly stabilized hypoxia-inducible factor α (HIF-α) and upregulated the expression of erythropoietin (EPO). Furthermore, oral administration of 22 dose-dependently stimulated erythropoiesis in vivo. Preliminary preclinical studies showed that 22 has good pharmacokinetic properties and an excellent safety profile, even at 10 times the efficacious dose (200 mg/kg). Taken together, these results indicate that 22 is a promising candidate for anemia treatment.


Asunto(s)
Anemia , Inhibidores de Prolil-Hidroxilasa , Humanos , Anemia/tratamiento farmacológico , Sitios de Unión , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Diseño de Fármacos , Conformación Molecular , Inhibidores de Prolil-Hidroxilasa/farmacología , Inhibidores de Prolil-Hidroxilasa/uso terapéutico , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo
3.
Eur J Med Chem ; 238: 114479, 2022 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-35675755

RESUMEN

Prolyl hydroxylase 2 (PHD2) is a key regulatory enzyme responsible for the degradation of hypoxia-inducible factor-α (HIF-α). Pharmacological inhibition of PHD2 stabilizes HIF-α and induces the production of endogenous erythropoietin (EPO), which is regarded as a promising strategy for the treatment of renal anemia. To date, a series of PHD2 inhibitors have been approved or advanced into clinical studies. In this study, we developed a new type of PHD2 inhibitors with the tetrahydropyridin-4-ylpicolinoylglycine scaffold by using a scaffold hopping strategy. Among them, compound 25 showed potent inhibition toward PHD2 with an IC50 of 6.55 ± 0.41 nM. Furthermore, compound 25 upregulated reticulocytes in C57BL/6 mice. The subacute toxicological assay demonstrated 25 has no obvious toxicity in vivo. Overall, compound 25 is a promising candidate for the treatment of renal anemia.


Asunto(s)
Anemia , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Enfermedades Renales , Inhibidores de Prolil-Hidroxilasa , Piridinas , Anemia/tratamiento farmacológico , Anemia/metabolismo , Animales , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/metabolismo , Ratones , Ratones Endogámicos C57BL , Procolágeno-Prolina Dioxigenasa/metabolismo , Inhibidores de Prolil-Hidroxilasa/farmacología , Piridinas/farmacología
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