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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.

Original publication

DOI

10.1021/jm2006782

Type

Journal article

Journal

J Med Chem

Publication Date

11/08/2011

Volume

54

Pages

5320 - 5334

Keywords

Animals, Antineoplastic Agents, Biological Availability, Cell Line, Drug Design, Enzyme Inhibitors, Humans, Immunologic Factors, Indoles, Kinetics, Mice, Neoplasms, Structure-Activity Relationship, Tryptophan Oxygenase