Synthesis and biological evaluation of biaryl alkyl ethers as inhibitors of IDO1

Jay A Markwalder; Aaron J Balog; David K Williams; Susheel J Nara; Ratnakar Reddy; Saumya Roy; Yadagiri Kanyaboina; Xin Li; Kathy Johnston; Yi Fan; Hal Lewis; Frank Marsilio; Chunhong Yan; David Critton; John A Newitt; Sarah C Traeger; Dauh-Rurng Wu; Maria N Jure-Kunkel; Lata Jayaraman; Tai-An Lin; Michael W Sinz; John T Hunt; Steven P Seitz

doi:10.1016/j.bmcl.2023.129280

Synthesis and biological evaluation of biaryl alkyl ethers as inhibitors of IDO1

Bioorg Med Chem Lett. 2023 May 15:88:129280. doi: 10.1016/j.bmcl.2023.129280. Epub 2023 Apr 11.

Authors

Jay A Markwalder¹, Aaron J Balog², David K Williams³, Susheel J Nara⁴, Ratnakar Reddy⁴, Saumya Roy⁵, Yadagiri Kanyaboina⁴, Xin Li², Kathy Johnston⁵, Yi Fan⁵, Hal Lewis⁵, Frank Marsilio², Chunhong Yan², David Critton², John A Newitt², Sarah C Traeger², Dauh-Rurng Wu², Maria N Jure-Kunkel⁵, Lata Jayaraman⁵, Tai-An Lin⁵, Michael W Sinz², John T Hunt⁵, Steven P Seitz⁵

Affiliations

¹ Research & Development, Bristol Myers Squibb, Route 206 & Province Line Road, Princeton, NJ 08543, United States. Electronic address: [email protected].
² Research & Development, Bristol Myers Squibb, Route 206 & Province Line Road, Princeton, NJ 08543, United States.
³ Research & Development, Bristol Myers Squibb, Route 206 & Province Line Road, Princeton, NJ 08543, United States. Electronic address: [email protected].
⁴ Discovery Chemistry, Biocon Bristol Myers Squibb Research & Development Center, Bangalore, India.
⁵ Former Bristol Myers Squibb Employee, United States.

PMID: 37054759
DOI: 10.1016/j.bmcl.2023.129280

Abstract

Starting from the dialkylaniline indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor lead 3 (IDO1 HeLa IC₅₀ = 7.0 nM), an iterative process of synthesis and screening led to cyclized analog 21 (IDO1 HeLa IC₅₀ = 3.6 nM) which maintained the high potency of 3 while addressing issues of lipophilicity, cytochrome P450 (CYP) inhibition, hERG (human potassium ion channel Kv11.1) inhibition, Pregnane X Receptor (PXR) transactivation, and oxidative metabolic stability. An x-ray crystal structure of a biaryl alkyl ether 11 bound to IDO1 was obtained. Consistent with our earlier results, compound 11 was shown to bind to the apo form of the enzyme.

Keywords: Indoleamine 2,3-dioxygenase 1; Medicinal chemistry.

MeSH terms

Enzyme Inhibitors* / chemistry
Ethers*
HeLa Cells
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Ethers
Indoleamine-Pyrrole 2,3,-Dioxygenase