Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model

  • J Med Chem. 2009 Dec 10;52(23):7364-7. doi: 10.1021/jm900518f.
Eddy W Yue  1 ,  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
Affiliations
  • 1. Incyte Corporation, Experimental Station, Route 141 and Henry Clay Road, Wilmington, Delaware 19880, USA.
PMID: 19507862 DOI: 10.1021/jm900518f
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.

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