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: Eddy W Yue, Brent Douty, Brian Wayland, Michael Bower, Xiangdong Liu, Lynn Leffet, Qian Wang, Kevin J Bowman, Michael J Hansbury, Changnian Liu, Min Wei, Yanlong Li, Richard Wynn, Timothy C Burn, Holly K Koblish, Jordan S Fridman, Brian Metcalf, Peggy A Scherle, Andrew P Combs
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 23 Pg. 7364-7 (Dec 10 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19507862 (Publication Type: Journal Article)

Chemical References

• Amidines
• Enzyme Inhibitors
• Indoleamine-Pyrrole 2,3,-Dioxygenase

Topics

• Amidines (chemistry, metabolism, pharmacology, therapeutic use)
• Animals
• Binding, Competitive
• Disease Models, Animal
• Disease Progression
• Drug Discovery
• Enzyme Inhibitors (chemistry, metabolism, pharmacology, therapeutic use)
• Gene Expression Regulation, Neoplastic (drug effects)
• HeLa Cells
• Humans
• Indoleamine-Pyrrole 2,3,-Dioxygenase (antagonists & inhibitors, chemistry, metabolism)
• Inhibitory Concentration 50
• Melanoma (drug therapy, enzymology, genetics, pathology)
• Mice
• Models, Molecular
• Molecular Conformation