4-Aryl-1,2,3-triazole: a novel template for a reversible methionine aminopeptidase 2 inhibitor, optimized to inhibit angiogenesis in vivo.
Inhibitors of human methionine aminopeptidase type 2 (hMetAP2) are of interest as potential treatments for cancer. A new class of small molecule reversible inhibitors of hMetAP2 was discovered and optimized, the 4-aryl-1,2,3-triazoles. Compound 24, a potent inhibitor of cobalt-activated hMetAP2, also inhibits human and mouse endothelial cell growth. Using a mouse matrigel model, this reversible hMetAP2 inhibitor was also shown to inhibit angiogenesis in vivo.
Kallander
Lara S
LS
GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. lara.s.kallander@gsk.com
Lu
Qing
Q
Chen
Wenfang
W
Tomaszek
Thaddeus
T
Yang
Guang
G
Tew
David
D
Meek
Thomas D
TD
Hofmann
Glenn A
GA
Schulz-Pritchard
Christina K
CK
Smith
Ward W
WW
Janson
Cheryl A
CA
Ryan
M Dominic
MD
Zhang
Gui-Feng
GF
Johanson
Kyung O
KO
Kirkpatrick
Robert B
RB
Ho
Thau F
TF
Fisher
Paul W
PW
Mattern
Michael R
MR
Johnson
Randall K
RK
Hansbury
Michael J
MJ
Winkler
James D
JD
Ward
Keith W
KW
Veber
Daniel F
DF
Thompson
Scott K
SK
D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003035:Cobalt / Q000378:metabolism; D003094:Collagen; D018360:Crystallography, X-Ray; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation; D006801:Humans; D007797:Laminin; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011509:Proteoglycans; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D014230:Triazoles; C059485:matrigel; D003035:Cobalt; D003094:Collagen; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases