Identification and optimization of a novel series of indoleamine 2,3-dioxygenase inhibitors

Jay A Markwalder; Steven P Seitz; Yuval Blat; Lisa Elkin; John T Hunt; Jonathan G Pabalan; Maria N Jure-Kunkel; Gregory D Vite; Kelly Covello

doi:10.1016/j.bmcl.2016.12.015

Identification and optimization of a novel series of indoleamine 2,3-dioxygenase inhibitors

Bioorg Med Chem Lett. 2017 Feb 1;27(3):582-585. doi: 10.1016/j.bmcl.2016.12.015. Epub 2016 Dec 7.

Authors

Jay A Markwalder¹, Steven P Seitz², Yuval Blat³, Lisa Elkin⁴, John T Hunt⁵, Jonathan G Pabalan⁵, Maria N Jure-Kunkel⁵, Gregory D Vite², Kelly Covello⁵

Affiliations

¹ Oncology Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States. Electronic address: jay.markwalder@bms.com.
² Oncology Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
³ Mechanistic Biochemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.
⁴ Lead Discovery & Optimization, Bristol-Myers Squibb Research and Development, Wallingford, CT 06492, United States.
⁵ Oncology Biology, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, United States.

PMID: 28003141
DOI: 10.1016/j.bmcl.2016.12.015

Abstract

The discovery of a series of structurally-novel biaryl urea IDO inhibitors is described. Optimization of a micromolar hit through iterative cycles of synthesis and screening in an assay measuring IDO-mediated intracellular conversion of tryptophan to kynurenine led to potent inhibitors with favorable selectivity and metabolic stability profiles.

Keywords: IDO; Immuno-oncology; Indoleamine 2,3-dioxygenase; Kynurenine.

MeSH terms

Animals
Carboxylic Acids / chemical synthesis
Carboxylic Acids / chemistry
Carboxylic Acids / pharmacology*
Dogs
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HeLa Cells
High-Throughput Screening Assays
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
Mice
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Molecular Structure
Structure-Activity Relationship
Urea / analogs & derivatives
Urea / chemistry
Urea / pharmacology*

Substances

Carboxylic Acids
Enzyme Inhibitors
Indoleamine-Pyrrole 2,3,-Dioxygenase
Urea