Discovery and development of a novel N-(3-bromophenyl)-{[(phenylcarbamoyl)amino]methyl}-N-hydroxythiophene-2-carboximidamide indoleamine 2,3-dioxygenase inhibitor using knowledge-based drug design

  • Eur J Med Chem. 2022 Feb 5;229:114043. doi: 10.1016/j.ejmech.2021.114043.
Teng-Kuang Yeh  1 ,  Jen-Shin Song  1 ,  Po-Wei Chang  1 ,  Jin-Chen Yu  2 ,  Chia-Hwa Chang  3 ,  Fang-Yu Liao  1 ,  Ya-Wen Tien  1 ,  Ramajayam Kuppusamy  1 ,  An-Siou Li  1 ,  Chi-Han Chen  1 ,  Chieh-Wen Chen  1 ,  Li-Mei Lin  1 ,  Hsin-Huei Chang  1 ,  Chih-Hsiang Huang  1 ,  Jau-Ying Yao  1 ,  Mine-Hsine Wu  1 ,  Yi-Hui Peng  1 ,  Ching-Cheng Hsueh  1 ,  Wen-Chi Hsiao  1 ,  Pei-Husan Chen  1 ,  Chin-Yu Lin  1 ,  Su-Huei Hsieh  1 ,  Chuan Shih  1 ,  Ming-Shiu Hung  4 ,  Su-Ying Wu  5 ,  Ching-Chuan Kuo  6 ,  Shau-Hua Ueng  7
Affiliations
  • 1. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan.
  • 2. Bio-Thera Solutions Ltd., Guangzhou, 510530, PR China.
  • 3. RDD lab, Inc., New Taipei City 248, Taiwan.
  • 4. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan. Electronic address: [email protected].
  • 5. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan. Electronic address: [email protected].
  • 6. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan. Electronic address: [email protected].
  • 7. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan; School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan. Electronic address: [email protected].
PMID: 34929581 DOI: 10.1016/j.ejmech.2021.114043
Abstract

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.

Keywords
Cancer immunotherapy; Indoleamine 2,3-dioxygenase; Knowledge-based drug design.
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