Carbamate analogues of fumagillin as potent, targeted inhibitors of methionine aminopeptidase-2.
J Med Chem
; 52(24): 8047-56, 2009 Dec 24.
Article
en En
| MEDLINE
| ID: mdl-19929003
Inhibition of methionine aminopeptidase-2 (MetAP2) represents a novel approach to antiangiogenic therapy. We describe the synthesis and activity of fumagillin analogues that address the pharmacokinetic and safety liabilities of earlier candidates in this compound class. Two-step elaboration of fumagillol with amines yielded a diverse series of carbamates at C6 of the cyclohexane spiroepoxide. The most potent of these compounds exhibited subnanomolar inhibition of cell proliferation in HUVEC and BAEC assays. Although a range of functionalities were tolerated at this position, alpha-trisubstituted amines possessed markedly decreased inhibitory activity, and this could be rationalized by modeling based on the known fumagillin-MetAP2 crystal structure. The lead compound resulting from these studies, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (R)-1-amino-3-methyl-1-oxobutan-2-ylcarbamate, (PPI-2458), demonstrated an improved pharmacokinetic profile relative to the earlier clinical candidate TNP-470, and has advanced into phase I clinical studies in non-Hodgkin's lymphoma and solid cancers.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Carbamatos
/
Metaloendopeptidasas
/
Ciclohexanos
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Ácidos Grasos Insaturados
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Aminopeptidasas
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos