Andryianau Gleb, Kowalski Michal, Piotrowicz Michal C, Rajkiewicz Adam A, Dymek Barbara, Sklepkiewicz Piotr L, Pluta Elzbieta, Stefaniak Filip, Czestkowski Wojciech, Olejniczak Sylwia, Mazur Marzena, Niedziejko Piotr, Koralewski Robert, Matyszewski Krzysztof, Gruza Mariusz, Zagozdzon Agnieszka, Salamon Magdalena, Rymaszewska Aleksandra, Welzer Mikolaj, Dzwonek Karolina, Golab Jakub, Olczak Jacek, Bartoszewicz Agnieszka, Golebiowski Adam
OncoArendi Therapeutics S.A., Żwirki i Wigury 101, 02-089 Warsaw, Poland.
Centre of New Technologies, University of Warsaw, Banacha 2C, 02-097 Warsaw, Poland.
ACS Med Chem Lett. 2020 Apr 24;11(6):1228-1235. doi: 10.1021/acsmedchemlett.0c00092. eCollection 2020 Jun 11.
Human acidic mammalian chitinase (hAMCase) is one of two true chitinases in humans, the function of which remains elusive. In addition to the defense against highly antigenic chitin and chitin-containing pathogens in the gastric and intestinal contents, AMCase has been implicated in asthma, allergic inflammation, and ocular pathologies. Potent and selective small-molecule inhibitors of this enzyme have not been identified to date. Here we describe structural modifications of compound , a previously developed inhibitor of mouse AMCase, leading to , which displays high activity and selectivity toward hAMCase. Significantly reduced off-target activity toward the human ether-à-go-go-related gene (hERG) and a good pharmacokinetic profile make a potential candidate for further preclinical development as well as a useful tool compound to study the physiological role of hAMCase.
人类酸性哺乳动物几丁质酶（hAMCase）是人类体内两种真正的几丁质酶之一，其功能仍不清楚。除了抵御胃和肠道内容物中具有高度抗原性的几丁质和含几丁质的病原体外，AMCase还与哮喘、过敏性炎症和眼部疾病有关。迄今为止，尚未发现该酶的强效和选择性小分子抑制剂。在此，我们描述了化合物（一种先前开发的小鼠AMCase抑制剂）的结构修饰，得到了化合物，其对hAMCase表现出高活性和选择性。对人类醚-à-去极化相关基因（hERG）的脱靶活性显著降低，以及良好的药代动力学特征，使得化合物成为进一步临床前开发的潜在候选物，也是研究hAMCase生理作用的有用工具化合物。
