2. Academic Validation
  3. Discovery of selective, orally bioavailable inhibitor of mouse chitotriosidase

Discovery of selective, orally bioavailable inhibitor of mouse chitotriosidase

  • Bioorg Med Chem Lett. 2018 Feb 1;28(3):310-314. doi: 10.1016/j.bmcl.2017.12.047.
Marzena Mazur 1,  Agnieszka Bartoszewicz 2,  Barbara Dymek 1,  Magdalena Salamon 1,  Gleb Andryianau 1,  Michał Kowalski 1,  Sylwia Olejniczak 1,  Krzysztof Matyszewski 1,  Elżbieta Pluta 1,  Bartłomiej Borek 1,  Filip Stefaniak 3,  Agnieszka Zagozdzon 1,  Marcin Mazurkiewicz 1,  Robert Koralewski 1,  Wojciech Czestkowski 1,  Michał Piotrowicz 1,  Piotr Niedziejko 1,  Mariusz M Gruza 1,  Karolina Dzwonek 1,  Adam Golebiowski 1,  Jakub Golab 4,  Jacek Olczak 1
Affiliations

Affiliations

  • 1 OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland.
  • 2 OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland. Electronic address: a.bartoszewicz@oncoarendi.com.
  • 3 OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland; Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, Ks. Trojdena 4, 02-109 Warsaw, Poland.
  • 4 OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland; Department of Immunology, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland.
PMID: 29292229 DOI: 10.1016/j.bmcl.2017.12.047
Abstract

This article describes our work towards the identification of a potent and selective inhibitor of mouse chitotriosidase (mCHIT1). A series of small molecule inhibitors of mCHIT1 and mAMCase have been developed from early lead compound 1. Examination of synthetized analogues led to discovery of several novel highly potent compounds. Among them compound 9 (OAT-2068) displays a remarkable 143-fold mCHIT1 vs. mAMCase selectivity. To explain the observed SAR molecular docking experiments were performed, which were in line with the experimental data from the enzymatic assays. Inhibitor 9 (OAT-2068) was found to have an excellent pharmacokinetic profile. This, together with high activity and selectivity, makes the compound an ideal and unique tool for studying the role of CHIT1 in biological models.

Keywords

Chitinase; Chitotriosidase; Fibrosis; Selective inhibitor; mCHIT1.

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