3-Amino-2-hydroxyamides and related compounds as inhibitors of methionine aminopeptidase-2.
Substituted 3-amino-2-hydroxyamides and related hydroxyamides and acylhydrazines were identified as inhibitors of human methionine aminopeptidase-2 (MetAP2). Examination of substituents through parallel synthesis and iterative structure-based design allowed the identification of potent inhibitors with good selectivity against MetAP1. Diacylhydrazine 3t (A-357300) was identified as an analogue displaying inhibition of methionine processing and cellular proliferation in human microvascular endothelial cells (HMVEC).
Sheppard
George S
GS
Abbott Laboratories, Global Pharmaceutical Research and Development, Cancer Research, 100 Abbott Park Road, Abbott Park, IL 60064, USA. george.sheppard@abbott.com
Wang
Jieyi
J
Kawai
Megumi
M
BaMaung
Nwe Y
NY
Craig
Richard A
RA
Erickson
Scott A
SA
Lynch
Linda
L
Patel
Jyoti
J
Yang
Fan
F
Searle
Xenia B
XB
Lou
Pingping
P
Park
Chang
C
Kim
Ki H
KH
Henkin
Jack
J
Lesniewski
Richard
R
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D001665:Binding Sites / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008715:Methionine / Q000187:drug effects; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure
D000577:Amides; D004791:Enzyme Inhibitors; D008715:Methionine; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases