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A Series of 2‐((1‐Phenyl‐1H‐imidazol‐5‐yl)methyl)‐1H‐indoles as Indoleamine 2,3‐Dioxygenase 1 (IDO1) Inhibitors
Author(s) -
Zheng Yong,
Stafford Paul M.,
Stover Kurt R.,
Mohan Darapaneni Chandra,
Gupta Mayuri,
Keske Eric C.,
Schiavini Paolo,
Villar Laura,
Wu Fan,
Kreft Alexander,
Thomas Kiersten,
Raaphorst Elana,
Pasangulapati Jagadeesh P.,
Alla Siva R.,
Sharma Simmi,
Mittapalli Ramana R.,
Sagamanova Irina,
Johnson Shea L.,
Reed Mark A.,
Weaver Donald F.
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100107
Subject(s) - chemistry , penetrant (biochemical) , indoleamine 2,3 dioxygenase , docking (animal) , pharmacology , indole test , stereochemistry , structure–activity relationship , combinatorial chemistry , biochemistry , medicine , in vitro , tryptophan , organic chemistry , amino acid , nursing
Abstract Indoleamine 2,3‐dioxygenase 1 (IDO1) is a promising therapeutic target in cancer immunotherapy and neurological disease. Thus, searching for highly active inhibitors for use in human cancers is now a focus of widespread research and development efforts. In this study, we report the structure‐based design of 2‐(5‐imidazolyl)indole derivatives, a series of novel IDO1 inhibitors which have been designed and synthesized based on our previous study using N 1‐substituted 5‐indoleimidazoles. Among these, we have identified one with a strong IDO1 inhibitory activity (IC 50 =0.16 μM, EC 50 =0.3 μM). Structural‐activity relationship (SAR) and computational docking simulations suggest that a hydroxyl group favorably interacts with a proximal Ser167 residue in Pocket A, improving IDO1 inhibitory potency. The brain penetrance of potent compounds was estimated by calculation of the Blood Brain Barrier (BBB) Score and Brain Exposure Efficiency (BEE) Score. Many compounds had favorable scores and the two most promising compounds were advanced to a pharmacokinetic study which demonstrated that both compounds were brain penetrant. We have thus discovered a flexible scaffold for brain penetrant IDO1 inhibitors, exemplified by several potent, brain penetrant, agents. With this promising scaffold, we provide herein a basis for further development of brain penetrant IDO1 inhibitors.