Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase.
Andryianau G, Kowalski M, Piotrowicz MC, Rajkiewicz AA, Dymek B, Sklepkiewicz PL, Pluta E, Stefaniak F, Czestkowski W, Olejniczak S, Mazur M, Niedziejko P, Koralewski R, Matyszewski K, Gruza M, Zagozdzon A, Salamon M, Rymaszewska A, Welzer M, Dzwonek K, Golab J, Olczak J, Bartoszewicz A, Golebiowski A.
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 <b>OAT-177</b>, a previously developed inhibitor of mouse AMCase, leading to <b>OAT-1441</b>, 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 <b>OAT-1441</b> a potential candidate for further preclinical development as well as a useful tool compound to study the physiological role of hAMCase.