1. Synthesis and biological evaluation of biaryl alkyl ethers as inhibitors of IDO1.
- Author
-
Markwalder JA, Balog AJ, Williams DK, Nara SJ, Reddy R, Roy S, Kanyaboina Y, Li X, Johnston K, Fan Y, Lewis H, Marsilio F, Yan C, Critton D, Newitt JA, Traeger SC, Wu DR, Jure-Kunkel MN, Jayaraman L, Lin TA, Sinz MW, Hunt JT, and Seitz SP
- Subjects
- Humans, Structure-Activity Relationship, HeLa Cells, Indoleamine-Pyrrole 2,3,-Dioxygenase, Enzyme Inhibitors chemistry, Ethers
- Abstract
Starting from the dialkylaniline indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor lead 3 (IDO1 HeLa IC
50 = 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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