Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors

Abstract

a b s t r a c tIndoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships (SAR) of a novel series of IDO inhibitors based on the indol-2-yl ethanone scaffold is described. In vitro and in vivo biological activities have been evaluated, leading to compounds with IC 50 values in the micromolar range in both tests. Introduction of small substituents in the 5-and 6-positions of the indole ring, indole N-methylation and variations of the aromatic side chain are all well tolerated. An iron coordinating group on the linker is a prerequisite for biological activity, thus corroborating the virtual screening results.

In Vitro Blood–Brain Barrier Models: Current and Perspective Technologies

“…This allows for rapid and inexpensive screening of novel lead drugs, which limit the need for labor‐intensive laboratory experiments and expensive clinical trials. Recently, this technique was used to discover potential inhibitors to an enzyme associated with cancer activity,115 which was then confirmed in vitro and in vivo 116. Several pharmaceutical companies (e.g., Roche) now use this technique as a routine part of the drug discovery process.…”

Immune Sculpting of Norepinephrine on MHC-I, B7-1, IDO and B7-H1 Expression and Regulation of Proliferation and Invasion in Pancreatic Carcinoma Cells

“…IDO, an enzyme of the kynurenine pathway of tryptophan catabolism, catalyzes the initial and rate-limiting step of the pathway, which consists of the oxidative cleavage of the pyrrole ring of the indole nucleus of L-Trp to yield N-formylkynurenine [7]. Emerging evidence suggests that during cancer progression, activation of the IDO pathway might act as a preferred nodal modifier pathway for immune escape.…”

In Vitro Cerebrovascular Modeling in the 21st Century: Current and Prospective Technologies

“…In the past, logBB was quantitatively related to a number of molecular descriptors like octanol/water partition coefficient (logP), molecular weight, molecular volume, dipolarity/polarizability, refraction index, hydrogen bond acceptor and donor number including the polar surface area (57). These molecular descriptors, in combination with different statistical methods, are used to build computational models which screen libraries of compounds (58); a technique which recently led to the discovery of promising new anticancer drugs (59) (60). In addition to the considerable advantages and benefits of in silico predictive models there are also limitations that need to be taken into consideration.…”