OncoArendi Therapeutics SA , Żwirki i Wigury 101 , 02-089 Warsaw , Poland.
Laboratory of Bioinformatics and Protein Engineering , International Institute of Molecular and Cell Biology in Warsaw , Ks. Trojdena 4 , 02-109 Warsaw , Poland.
J Med Chem. 2019 Aug 8;62(15):7126-7145. doi: 10.1021/acs.jmedchem.9b00681. Epub 2019 Jul 23.
Acidic mammalian chitinase (AMCase) and chitotriosidase-1 (CHIT1) are two enzymatically active proteins produced by mammals capable of cleaving the glycosidic bond in chitin. Based on the clinical findings and animal model studies, involvement of chitinases has been suggested in several respiratory system diseases including asthma, COPD, and idiopathic pulmonary fibrosis. Exploration of structure-activity relationships within the series of 1-(3-amino-1-1,2,4-triazol-5-yl)-piperidin-4-amines, which was earlier identified as a scaffold of potent AMCase inhibitors, led us to discover highly active dual (i.e., AMCase and CHIT1) inhibitors with very good pharmacokinetic properties. Among them, compound was shown to reduce the total number of cells in bronchoalveolar lavage fluid of mice challenged with house dust mite extract after oral administration (50 mg/kg, qd). In addition, affinity toward the hERG potassium channel of compound was significantly reduced when compared to the earlier reported chitinase inhibitors.
酸性哺乳动物几丁质酶（AMCase）和壳三糖苷酶-1（CHIT1）是两种由哺乳动物产生的具有酶活性的蛋白质，能够切割几丁质中的糖苷键。基于临床发现和动物模型研究，几丁质酶的参与已被提出在几种呼吸系统疾病，包括哮喘、COPD 和特发性肺纤维化。在一系列 1-（3-氨基-1-1,2,4-三唑-5-基）-哌啶-4-胺中探索结构-活性关系，这些化合物先前被确定为强效 AMCase 抑制剂的支架，导致我们发现了具有非常好的药代动力学性质的高活性双（即 AMCase 和 CHIT1）抑制剂。其中，化合物在口服（50mg/kg，qd）后可减少尘螨提取物刺激的小鼠支气管肺泡灌洗液中的总细胞数。此外，与早期报道的几丁质酶抑制剂相比，化合物对 hERG 钾通道的亲和力显著降低。
