Carbamate Analogues of Fumagillin as Potent, Targeted Inhibitors of Methionine Aminopeptidase-2

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• 作者：Christopher C. Arico-Muendel ; Dennis R. Benjamin ; Teresa M. Caiazzo ; Paolo A. Centrella ; Brooke D. Contonio ; Charles M. Cook ; Elisabeth G. Doyle ; Gerhard Hannig ; Matthew T. Labenski ; Lily L. Searle ; K
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：December 24, 2009
• 年：2009
• 卷：52
• 期：24
• 页码：8047-8056
• 全文大小：916K
• 年卷期：v.52,no.24(December 24, 2009)
• ISSN：1520-4804

文摘

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, α-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.