Atropisomerism by Design: Discovery of a Selective and Stable Phosphoinositide 3-Kinase (PI3K) ß Inhibitor.
J Med Chem
; 61(15): 6858-6868, 2018 Aug 09.
Article
en En
| MEDLINE
| ID: mdl-30015489
ABSTRACT
Atropisomerism is a type of axial chirality in which enantiomers or diastereoisomers arise due to hindered rotation around a bond axis. In this manuscript, we report a case in which torsional scan studies guided the thoughtful creation of a restricted axis of rotation between two heteroaromatic systems of a phosphoinositide 3-kinase (PI3K) ß inhibitor, generating a pair of atropisomeric compounds with significantly different pharmacological and pharmacokinetic profiles. Emblematic of these differences, the metabolism of inactive ( M)-28 is primarily due to the cytosolic enzyme aldehyde oxidase, while active ( P)-28 has lower affinity for aldehyde oxidase, resulting in substantially better metabolic stability. Additionally, we report torsional scan and experimental studies used to determine the barriers of rotation of this novel PI3Kß inhibitor.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Diseño de Fármacos
/
Inhibidores Enzimáticos
/
Inhibidores de las Quinasa Fosfoinosítidos-3
Límite:
Animals
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos