Carbamate analogues of fumagillin as potent, targeted inhibitors of methionine aminopeptidase-2.
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.
Arico-Muendel
Christopher C
CC
Praecis Pharmaceuticals, Inc., Waltham, MA 02451-1420, USA. christopher.c.arico-muendel@gsk.com
Benjamin
Dennis R
DR
Caiazzo
Teresa M
TM
Centrella
Paolo A
PA
Contonio
Brooke D
BD
Cook
Charles M
CM
Doyle
Elisabeth G
EG
Hannig
Gerhard
G
Labenski
Matthew T
MT
Searle
Lily L
LL
Lind
Kenneth
K
Morgan
Barry A
BA
Olson
Gary
G
Paradise
Christopher L
CL
Self
Christopher
C
Skinner
Steven R
SR
Sluboski
Barbara
B
Svendsen
Jennifer L
JL
Thompson
Charles D
CD
Westlin
William
W
White
Kerry F
KF
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
D000596:Amino Acids; D002219:Carbamates; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D012717:Sesquiterpenes; C026211:fumagillin; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases