Acidic Mammalian Chitinase (AMCase) is a representative of GH18 glycoside hydrolases family and is one of two proteins in mammals with chitinolytic activity preserved throughout the evolution (together with chitotriosidase - CHIT1).<br/>Elevated AMCase levels in lungs have been correlated with type 2 inflammation development in the animal models of asthma. Our recent studies demonstrated that selective AMCase inhibition by OAT-177 exhibits strong anti-inflammatory effect in House Dust Mite (HDM) - induced asthma model in mice. Moreover, increased amounts of AMCase have been found in the samples from allergic patients.<br/>Herein, we report our SAR studies based on structure-guided scaffold hopping and lead optimization that resulted in the discovery of an improved compound. OAT-1441 is a single nanomolar inhibitor of human AMCase, which displays excellent hAMCase/hCHIT1 as well as hAMCase/hERG selectivity. In comparison to previously reported data for allosamidin, Wyeth-1, bisdionin F and argifin, OAT-1441 shows improved drug-like properties and pharmacokinetic parameters in rats, which make it suitable for oral administration.

Discovery of OAT-1441: Highly active, selective, and orally bioavailable inhibitor of human AMCase

2019 Fall National Meeting

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