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Inhibitors of the coagulation factor XIIa (FXIIa) are attractive to detail the roles of this protease in hemostasis and thrombosis, to suppress artifact due to contact pathway activation in blood coagulation assays, and they are promising as antithrombotic therapy. The 3-carboxamide coumarins have been previously described as small-molecular-weight FXIIa inhibitors. In this study, we report a structure-activity relationship (SAR) study around this scaffold with the aim to discover new selective FXIIa inhibitors with an improved physico-chemical profile. To better understand these SAR, docking experiments were undertaken. For this purpose, we built an original hybrid model of FXIIa. This model has the advantage to gather the best features from the recently published crystal structure of FXIIa in its zymogen form and a more classical homology model. Results with the hybrid model are encouraging as they help understanding the activity and selectivity of our best compounds.

Highly functionalized 5-bromo-2-amino-1,3-thiazoles bearing various substituents could be easily prepared by a rapid and efficient one-pot method, using simple starting materials and mild conditions while avoiding the use of metal catalysts or inconvenient reagents such as elemental halogens. These useful products can serve as starting materials for other reactions or as pharmacologically interesting compounds. In our work we have shown that the resulting 5-bromothiazole compounds could lead to monoacylglycerol lipase (MAGL) inhibition in the μM range.

Introduction: The inhibition of indoleamine 2,3-dioxygenase (IDO) has emerged as a key area in cancer immunotherapy in the past decade. Despite the large variety of potential inhibitors screened so far, the number of active scaffolds remains limited. Areas covered: All relevant patent literature published between 2008 and 2012 is reviewed. Representative examples are given for each patent and/or class of compounds along with data (if available) on their inhibitory activity. The presentation is deepened by additional data published in peer-reviewed literature. Expert opinion: Key events that stimulated the search of IDO inhibitors are presented. To date, however, the number of available scaffolds remains limited with only one confirmed inhibitor (from Incyte Corp.) in the clinic. Major challenges in the search for IDO inhibitors are discussed as well as the relevance of selectivity of IDO inhibition versus inhibition of tryptophan 2,3-dioxygenase. © 2013 Informa UK, Ltd.

Three isomers of chloro-3-(2-pyridin-3-ylvinyl)-1H-indole were synthesized and tested as inhibitors of human tryptophan 2,3-dioxygenase (hTDO). The crystal structures of two of them were solved by X-ray diffraction. The solubility of the molecules also was determined experimentally. The molecular electrostatic potentials and dipole moments of the three isomers were calculated by ab initio quantum mechanics (HF/6-311G). The single crystal X-ray analyses reveal non-planar structures. This non-coplanarity is retained during docking of the compounds into a model of hTDO, the molecular target of this series. The position of the Cl atom does not significantly affect the electronic delocalization. Nevertheless, the position of the Cl atom produces a local variation of bond lengths inducing different dipole moments for these isomers. Variations in dipole moments are consistent with the different melting points and crystal packings. Differences in aqueous solubilities are best explained by subtle changes in H-bonds resulting from different accessibilities of the indole NH's due to steric effects of the Cl substituent. The non-coplanarity plays an important role in the crystalline packing of the molecules in contrast to the position of the Cl. This study leads to a better understanding of the structural and electronic characteristics of this chemical series and can potentially help to better understand their inhibitory activity. © 2012 Elsevier Masson SAS. All rights reserved.

Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure-activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His(55) and Thr(254) residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K(i) = 5.5 μM), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.

Indoleamine 2,3-dioxygenase (IDO) is an important new therapeutic target for the treatment of cancer. With the aim of discovering novel IDO inhibitors, a virtual screen was undertaken and led to the discovery of the keto-indole derivative 1a endowed with an inhibitory potency in the micromolar range. Detailed kinetics were performed and revealed an uncompetitive inhibition profile. Preliminary SARs were drawn in this series and corroborated the putative binding orientation as suggested by docking. © 2011 Elsevier Masson SAS. All rights reserved.

Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance.1 IDO inhibition has been an active area of research in drug development for a number of years.2 Recently, our group has shown that tryptophan 2,3 dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is as well expressed in many tumors preventing their rejection by locally depleting tryptophan.3 The role of tryptophan catabolites was demonstrated by another group.4 Herein, we report the syntheses and structure-activity studies around a series of 3-(2-(pyridyl)ethenyl)indoles.5 Some 80 novel heterocyclic compounds were synthesized. Their TDO inhibitory potency was evaluated and rationalized by molecular modeling studies. The best candidate in terms of potency, selectivity, solubility and oral bioavailability was evaluated in a preclinical model in mice. Upon systemic treatment, the compound reversed TDO-mediated tumoral immune resistance.6 References This work was supported in part by FNRS-Télévie (7.4.543.07). 1) Uyttenhove, C., et al, Nat. Med. 2003, 9, 1269-1274. 2) Macchiarulo, A., et al, Amino Acids 2009, 37, 219-229; Röhrig, U. F., et al, J. Med. Chem. 2010, 53, 1172-1189. 3) Van den Eynde, B., et al, WO2010008427, 2010. 4) Opitz, C. A., et al, Nature 2011, 478, 197-203. 5) Dolusic, E., et al, J. Med. Chem. 2011, 54, 5320-5334. 6) Pilotte, L., et al, Proc. Natl. Acad. Sci. USA 2012, 109, 2497 - 2502.

Tetrapyrrole macrocycles, of which the pyrroles are connected by sp2 centers, were readily obtained from porphyrin tetraphenols by air oxidation under basic conditions, followed by N-alkylation. The degree of N-alkylation could be controlled and either di- or tetraalkylated derivatives are obtained in high yields. (C) 2003 Elsevier Science Ltd. All rights reserved.

Biotinylated indoles were prepared for application as bifunctional probes for the detection of indole-binding proteins which participate in the life processes of humans, animals, plants, and bacteria. The indole nucleus was functionalized, at ring positions 3, 5, or 6, by attachment of a 2-aminoethyl group, which was then coupled to the carboxyl moiety of biotin, via a spacer composed of 3 or 4 concatenated beta-alanine residues. The constructs thus obtained were able to inhibit tryptophanase activity, similarly to indole in a concentration-dependent manner. They also bound strongly to lysozyme and weakly to bovine and human serum albumins, in accordance with the known affinities of these proteins for indole and 3-(2-aminoethyl)indole (tryptamine). The biotin end of the protein-bound bifunctional probes could then be detected by coupling to (strept)avidin conjugated to alkaline phosphatase or horseradish peroxidase, followed by incubation with substrates which are converted by these enzymes to intensely colored or chemiluminescent products.