Development of Dual Chitinase Inhibitors as Potential New Treatment for Respiratory System Diseases

• Published in: Journal of medicinal chemistry 2019-08, Vol.62 (15), p.7126-7145
• Main Authors: Mazur, Marzena, Dymek, Barbara, Koralewski, Robert, Sklepkiewicz, Piotr, Olejniczak, Sylwia, Mazurkiewicz, Marcin, Piotrowicz, Michał, Salamon, Magdalena, Jędrzejczak, Karol, Zagozdzon, Agnieszka, Czestkowski, Wojciech, Matyszewski, Krzysztof, Borek, Bartłomiej, Bartoszewicz, Agnieszka, Pluta, Elżbieta, Rymaszewska, Aleksandra, Mozga, Witold, Stefaniak, Filip, Dobrzański, Paweł, Dzwonek, Karolina, Golab, Jakub, Golebiowski, Adam, Olczak, Jacek
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b00681

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-1H-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 30 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 30 was significantly reduced when compared to the earlier reported chitinase inhibitors.