Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability.
ACS Med Chem Lett
; 6(5): 596-601, 2015 May 14.
Article
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| MEDLINE
| ID: mdl-26005540
ABSTRACT
Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochemical properties. Specifically, incorporation of fluorine enabled design of metabolically less liable lipophilic alkyl substituents to increase potency without compromising the sp(3)-character. The lead compound 21 (PF-06442609) displayed a favorable rodent pharmacokinetic profile, and robust reductions of brain Aß42 and Aß40 were observed in a guinea pig time-course experiment.
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Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
ACS Med Chem Lett
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos