Optimization of Orally Bioavailable PI3Kδ Inhibitors and Identification of Vps34 as a Key Selectivity Target.
J Med Chem
; 63(2): 638-655, 2020 01 23.
Article
en En
| MEDLINE
| ID: mdl-31855425
ABSTRACT
Optimization of a lead series of PI3Kδ inhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kδ, and compound 19 was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδ over Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposure levels to compound 19.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Fosfatidilinositol 3-Quinasa Clase I
/
Fosfatidilinositol 3-Quinasas Clase III
/
Inhibidores de las Quinasa Fosfoinosítidos-3
Tipo de estudio:
Diagnostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2020
Tipo del documento:
Article