期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 28, 期 3, 页码 310-314出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.12.047
关键词
Chitotriosidase; Chitinase; Selective inhibitor; mCHIT1; Fibrosis
资金
- project - Preclinical research and clinical trials of a first-in-class development candidate in therapy of asthma and inflammatory bowel disease - acronym IBD
- National Centre for Research and Development
This article describes our work towards the identification of a potent and selective inhibitor of mouse chitotriosidase (mCHIT1). A series of small molecule inhibitors of mCHIT1 and mAMCase have been developed from early lead compound 1. Examination of synthetized analogues led to discovery of several novel highly potent compounds. Among them compound 9 (OAT-2068) displays a remarkable 143-fold mCHIT1 vs. mAMCase selectivity. To explain the observed SAR molecular docking experiments were performed, which were in line with the experimental data from the enzymatic assays. Inhibitor 9 (OAT-2068) was found to have an excellent pharmacokinetic profile. This, together with high activity and selectivity, makes the compound an ideal and unique tool for studying the role of CHIT1 in biological models. (C) 2017 Elsevier Ltd. All rights reserved.
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