2. Academic Validation
  3. Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase

Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase

  • ACS Med Chem Lett. 2020 Apr 24;11(6):1228-1235. doi: 10.1021/acsmedchemlett.0c00092.
Gleb Andryianau 1,  Michal Kowalski 1,  Michal C Piotrowicz 1,  Adam A Rajkiewicz 1 2,  Barbara Dymek 1,  Piotr L Sklepkiewicz 1,  Elzbieta Pluta 1,  Filip Stefaniak 1 3,  Wojciech Czestkowski 1,  Sylwia Olejniczak 1,  Marzena Mazur 1,  Piotr Niedziejko 1,  Robert Koralewski 1,  Krzysztof Matyszewski 1,  Mariusz Gruza 1,  Agnieszka Zagozdzon 1,  Magdalena Salamon 1,  Aleksandra Rymaszewska 1,  Mikolaj Welzer 1,  Karolina Dzwonek 1,  Jakub Golab 1 4,  Jacek Olczak 1,  Agnieszka Bartoszewicz 1,  Adam Golebiowski 1
Affiliations

Affiliations

  • 1 OncoArendi Therapeutics S.A., Żwirki i Wigury 101, 02-089 Warsaw, Poland.
  • 2 Centre of New Technologies, University of Warsaw, Banacha 2C, 02-097 Warsaw, Poland.
  • 3 Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Ks. Trojdena 4, 02-109 Warsaw, Poland.
  • 4 Department of Immunology, Medical University of Warsaw, Nielubowicza 5, 02-097 Warsaw, Poland.
PMID: 32551005 DOI: 10.1021/acsmedchemlett.0c00092
Abstract

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.

Figures
Products