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Identification of Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Based on a Phenylimidazole Scaffold.

ABSTRACT: Inhibition of indoleamine 2,3-dioxygenase (IDO1) is an attractive immunotherapeutic approach for the treatment of a variety of cancers. Dysregulation of this enzyme has also been implicated in other disorders including Alzheimer's disease and arthritis. Herein, we report the structure-based design of two related series of molecules: N1-substituted 5-indoleimidazoles and N1-substituted 5-phenylimidazoles. The latter (and more potent) series was accessed through an unexpected rearrangement of an imine intermediate during a Van Leusen imidazole synthesis reaction. Evidence for the binding modes for both inhibitor series is supported by computational and structure-activity relationship studies.

SUBMITTER: Brant MG

PROVIDER: S-EPMC5807880 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Identification of Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Based on a Phenylimidazole Scaffold.

Brant Michael G MG Goodwin-Tindall Jake J Stover Kurt R KR Stafford Paul M PM Wu Fan F Meek Autumn R AR Schiavini Paolo P Wohnig Stephanie S Weaver Donald F DF

ACS medicinal chemistry letters 20180111 2

Inhibition of indoleamine 2,3-dioxygenase (IDO1) is an attractive immunotherapeutic approach for the treatment of a variety of cancers. Dysregulation of this enzyme has also been implicated in other disorders including Alzheimer's disease and arthritis. Herein, we report the structure-based design of two related series of molecules: <i>N</i>1-substituted 5-indoleimidazoles and <i>N</i>1-substituted 5-phenylimidazoles. The latter (and more potent) series was accessed through an unexpected rearran ...[more]

PMID: 29456801

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