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; Kenneth Lind; Barry A. Morgan; Gary Olson; Christopher L. Paradise; Christopher Self; Steven R. Skinner; Barbara Sluboski; Jennifer L. Svendsen; Charles D. Thompson; William Westlin; Kerry F. White
J. Med. Chem., 2009, 52, 24, 8047-8056
https://doi.org/10.1021/jm901260k

Abstract

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.