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Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators
Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators
- Source :
- Journal of Medicinal Chemistry. 54(15):5320-5334
- Publication Year :
- 2011
- Publisher :
- American Chemical Society, 2011.
-
Abstract
- 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.
- Subjects :
- Indoles
Biological Availability
Antineoplastic Agents
Pharmacology
Tryptophan 2 3 dioxygenase
Immune tolerance
Cell Line
Mice
Structure-Activity Relationship
Neoplasms
Drug Discovery
Structure–activity relationship
Animals
Humans
Immunologic Factors
Enzyme Inhibitors
Chemistry
Tryptophan
Tryptophan degradation
Tryptophan Oxygenase
Bioavailability
Kinetics
Biochemistry
Drug development
Cell culture
Drug Design
Molecular Medicine
Subjects
Details
- Language :
- English
- ISSN :
- 00222623
- Volume :
- 54
- Issue :
- 15
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....2e6a2bcd6407d829fe9ec4a24a0b478e
- Full Text :
- https://doi.org/10.1021/jm2006782