期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 229, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.114043
关键词
Knowledge-based drug design; Cancer immunotherapy; Indoleamine 2,3-dioxygenase
资金
- Ministry of Science and Technology, Taiwan [MOST 105-2325-B-400-017]
- Ministry of Health and Welfare [MOHW103-TDU-212-114006]
This study describes the development of two series of ID01 inhibitors and the improvement in cellular activity and pharmacokinetic properties of these compounds. Compound 27a showed significant in vivo target inhibition and this strategy can be applied to discover ID01 inhibitors for other diseases.
Indoleamine 2,3-dioxygenase-1 (IDO1) is a potential target for the next generation of cancer immunotherapies. We describe the development of two series of IDO1 inhibitors incorporating a N-hydroxy-thiophene-carboximidamide core generated by knowledge-based drug design. Structural modifications to improve the cellular activity and pharmacokinetic (PK) properties of the compounds synthesized, including extension of the side chain of the N-hydroxythiophene-2-carboximidamide core, resulted in compound 27a, a potent IDO1 inhibitor which demonstrated significant (51%) in vivo target inhibition on IDO1 in a human SK-OV-3 ovarian xenograft tumor mouse model. This strategy is expected to be applicable to the discovery of additional IDO1 inhibitors for the treatment of other diseases susceptible to modulation of IDO1. (c) 2021 Elsevier Masson SAS. All rights reserved.
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