Open AccessBenzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase
Author(s) -
Gleb Andryianau,
Michał Kowalski,
Michał Piotrowicz,
Adam A. Rajkiewicz,
Barbara Dymek,
Piotr Sklepkiewicz,
Elżbieta Pluta,
Filip Stefaniak,
Wojciech Czestkowski,
Sylwia Olejniczak,
Marzena Mazur,
Piotr Niedziejko,
Robert Koralewski,
Krzysztof Matyszewski,
Mariusz Gruza,
Agnieszka Zagożdżon,
Magdalena Salamon,
Aleksandra Rymaszewska,
Mikolaj Welzer,
Karolina Dzwonek,
Jakub Gołąb,
Jacek Olczak,
Agnieszka Bartoszewicz,
Adam Gołębiowski
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00092
Subject(s) - chitinase , herg , chitin , enzyme , chemistry , bioavailability , biochemistry , small molecule , pharmacology , biology , biophysics , potassium channel , chitosan
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 OAT-177 , a previously developed inhibitor of mouse AMCase, leading to OAT-1441 , 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 OAT-1441 a potential candidate for further preclinical development as well as a useful tool compound to study the physiological role of hAMCase.