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Metabolites of PPI-2458, a selective, irreversible inhibitor of methionine aminopeptidase-2: structure determination and In vivo activity

Arico-Muendel, Christopher C and Belanger, Bruce and Benjamin, Dennis and Blanchette, Heather S and Caiazzo, Teresa M and Centrella, Paolo A and DeLorey, Jennifer and Doyle, Elisabeth G and Gradhand, Ulrike and Griffin, Sarah T and Hill, Susan and Labenski, Matthew T and Morgan, Barry A and O'Donovan, Gary and Prasad, Kavirayani and Skinner, Steven and Taghizadeh, Nazbeh and Thompson, Charles D and Wakefield, James and Westlin, William and White, Kerry F (2013) Metabolites of PPI-2458, a selective, irreversible inhibitor of methionine aminopeptidase-2: structure determination and In vivo activity. In: Drug Metabolism and Disposition, 41 (4). pp. 814-826.

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Official URL: http://dx.doi.org/10.1124/dmd.112.048355

Abstract

The natural product fumagillin exhibits potent antiproliferative and antiangiogenic properties. The semisynthetic analog PPI-2458, (3R,4S,5S,6R)-5-methoxy-4-(2R,3R)-2-methyl-3-(3-methylbut-2-enyl) oxiran-2-yl]-1-oxaspiro2.5]octan-6-yl] N-(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate, demonstrates rapid inactivation of its molecular target, methionine aminopeptidase-2 (MetAP2), and good efficacy in several rodent models of cancer and inflammation with oral dosing despite low apparent oral bioavailability. To probe the basis of its in vivo efficacy, the metabolism of PPI-2458 was studied in detail. Reaction phenotyping identified CYP3A4/5 as the major source of metabolism in humans. Six metabolites were isolated from liver microsomes and characterized by mass spectrometry and nuclear resonance spectroscopy, and their structures were confirmed by chemical synthesis. The synthetic metabolites showed correlated inhibition of MetAP2 enzymatic activity and vascular endothelial cell growth. In an ex vivo experiment, MetAP2 inhibition in white blood cells, thymus, and lymph nodes in rats after single dosing with PPI-2458 and the isolated metabolites was found to correlate with the in vitro activity of the individual species. In a phase 1 clinical study, PPI-2458 was administered to patients with non-Hodgkin lymphoma. At 15 mg administered orally every other day, MetAP2 in whole blood was 80% inactivated for up to 48 hours, although the exposure of the parent compound was only similar to 10% that of the summed cytochrome P450 metabolites. Taken together, the data confirm the participation of active metabolites in the in vivo efficacy of PPI-2458. The structures define a metabolic pathway for PPI-2458 that is distinct from that of TNP-470 ((3R, 4S, 5S, 6R)-5-methoxy-4-(2R, 3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro2.5]octan-6 -yl] N-(2-chloroacetyl)carbamate). The high level of MetAP2 inhibition achieved in vivo supports the value of fumagillin-derived therapeutics for angiogenic diseases.

Item Type: Journal Article
Additional Information: Copyright of this article belongs to American Society for Pharmacology and Experimental Therapeutics.
Department/Centre: Division of Chemical Sciences > Organic Chemistry
Depositing User: Francis Jayakanth
Date Deposited: 12 Apr 2013 06:12
Last Modified: 12 Apr 2013 06:12
URI: http://eprints.iisc.ac.in/id/eprint/46299

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