Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model.
A hydroxyamidine chemotype has been discovered as a key pharmacophore in novel inhibitors of indoleamine 2,3-dioxygenase (IDO). Optimization led to the identification of 5l, which is a potent (HeLa IC(50) = 19 nM) competitive inhibitor of IDO. Testing of 5l in mice demonstrated pharmacodynamic inhibition of IDO, as measured by decreased kynurenine levels (>50%) in plasma and dose dependent efficacy in mice bearing GM-CSF-secreting B16 melanoma tumors.
Yue
Eddy W
EW
Incyte Corporation, Experimental Station, Route 141 and Henry Clay Road, Wilmington, Delaware 19880, USA.
Douty
Brent
B
Wayland
Brian
B
Bower
Michael
M
Liu
Xiangdong
X
Leffet
Lynn
L
Wang
Qian
Q
Bowman
Kevin J
KJ
Hansbury
Michael J
MJ
Liu
Changnian
C
Wei
Min
M
Li
Yanlong
Y
Wynn
Richard
R
Burn
Timothy C
TC
Koblish
Holly K
HK
Fridman
Jordan S
JS
Metcalf
Brian
B
Scherle
Peggy A
PA
Combs
Andrew P
AP
D000578:Amidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001667:Binding, Competitive; D004195:Disease Models, Animal; D018450:Disease Progression; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation
D000578:Amidines; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase