title: Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model.
abstract: 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.
authors.affiliation: Incyte Corporation, Experimental Station, Route 141 and Henry Clay Road, Wilmington, Delaware 19880, USA.
authors.forename: Eddy W
authors.initials: EW
authors.lastname: Yue
authors.forename: Brent
authors.initials: B
authors.lastname: Douty
authors.forename: Brian
authors.initials: B
authors.lastname: Wayland
authors.forename: Michael
authors.initials: M
authors.lastname: Bower
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Liu
authors.forename: Lynn
authors.initials: L
authors.lastname: Leffet
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Bowman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hansbury
authors.forename: Changnian
authors.initials: C
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Li
authors.forename: Richard
authors.initials: R
authors.lastname: Wynn
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Burn
authors.forename: Holly K
authors.initials: HK
authors.lastname: Koblish
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Fridman
authors.forename: Brian
authors.initials: B
authors.lastname: Metcalf
authors.forename: Peggy A
authors.initials: PA
authors.lastname: Scherle
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Combs
mesh_terms: 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
chemical_list: D000578:Amidines; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase