Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ-PI3Kδ Dual Inhibitors.
J Med Chem
; 62(10): 4936-4948, 2019 05 23.
Article
em En
| MEDLINE
| ID: mdl-31033293
ABSTRACT
An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Descoberta de Drogas
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Classe I de Fosfatidilinositol 3-Quinases
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Classe Ib de Fosfatidilinositol 3-Quinase
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Inibidores de Fosfoinositídeo-3 Quinase
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article