title: Carbamate analogues of fumagillin as potent, targeted inhibitors of methionine aminopeptidase-2.
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.
authors.affiliation: Praecis Pharmaceuticals, Inc., Waltham, MA 02451-1420, USA. christopher.c.arico-muendel@gsk.com
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Arico-Muendel
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Benjamin
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Caiazzo
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Centrella
authors.forename: Brooke D
authors.initials: BD
authors.lastname: Contonio
authors.forename: Charles M
authors.initials: CM
authors.lastname: Cook
authors.forename: Elisabeth G
authors.initials: EG
authors.lastname: Doyle
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hannig
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Labenski
authors.forename: Lily L
authors.initials: LL
authors.lastname: Searle
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lind
authors.forename: Barry A
authors.initials: BA
authors.lastname: Morgan
authors.forename: Gary
authors.initials: G
authors.lastname: Olson
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Paradise
authors.forename: Christopher
authors.initials: C
authors.lastname: Self
authors.forename: Steven R
authors.initials: SR
authors.lastname: Skinner
authors.forename: Barbara
authors.initials: B
authors.lastname: Sluboski
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Svendsen
authors.forename: Charles D
authors.initials: CD
authors.lastname: Thompson
authors.forename: William
authors.initials: W
authors.lastname: Westlin
authors.forename: Kerry F
authors.initials: KF
authors.lastname: White
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D002219:Carbamates / Q000737:chemistry* / Q000494:pharmacology*; D002417:Cattle; D048708:Cell Growth Processes / Q000187:drug effects; D003510:Cyclohexanes / Q000737:chemistry* / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005231:Fatty Acids, Unsaturated / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D002219:Carbamates; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D012717:Sesquiterpenes; C026211:fumagillin; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases