Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis.
ACS Med Chem Lett
; 6(8): 913-8, 2015 Aug 13.
Article
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| MEDLINE
| ID: mdl-26288693
ABSTRACT
Diverse biological roles for mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) have necessitated the identification of potent inhibitors in order to study its function in various disease contexts. In particular, compounds that can be used to carry out such studies in vivo would be critical for elucidating the potential for therapeutic intervention. A structure-based design effort coupled with property-guided optimization directed at minimizing the ability of the inhibitors to cross into the CNS led to an advanced compound 13 (GNE-495) that showed excellent potency and good PK and was used to demonstrate in vivo efficacy in a retinal angiogenesis model recapitulating effects that were observed in the inducible Map4k4 knockout mice.
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Colección:
01-internacional
Banco de datos:
MEDLINE
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En
Revista:
ACS Med Chem Lett
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos