Carbamate analogues of fumagillin as potent, targeted inhibitors of methionine aminopeptidase-2

Journal of Medicinal Chemistry
Christopher Arico-MuendelKerry F White

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, 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.

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Citations

May 3, 2013·Journal of Medicinal Chemistry·Feiran ZhangJun O Liu
Jan 31, 2013·Journal of Natural Products·Marieke VansteelandtOlivier Grovel
Mar 14, 2014·Journal of Agricultural and Food Chemistry·Johan P van den HeeverStephen F Pernal
Jun 20, 2012·Nanomedicine·Dipanjan PanGregory M Lanza
Apr 9, 2015·Medicinal Research Reviews·Alexander KornienkoRobert Kiss
Apr 11, 2013·ACS Medicinal Chemistry Letters·Christopher C Arico-MuendelKerry F White
Jun 8, 2017·World Journal of Biological Chemistry·Yie-Hwa Chang
Jan 29, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Christopher C Arico-MuendelKerry F White
Feb 19, 2021·International Journal for Parasitology. Drugs and Drug Resistance·Alexander Y F LamSamantha J Emery-Corbin

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