2. Academic Validation
  3. Discovery of OATD-01, a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis

Discovery of OATD-01, a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis

  • J Med Chem. 2020 Dec 24;63(24):15527-15540. doi: 10.1021/acs.jmedchem.0c01179.
Robert Koralewski 1,  Barbara Dymek 1,  Marzena Mazur 1,  Piotr Sklepkiewicz 1,  Sylwia Olejniczak 1,  Wojciech Czestkowski 1,  Krzysztof Matyszewski 1,  Gleb Andryianau 1,  Piotr Niedziejko 1,  Michal Kowalski 1,  Mariusz Gruza 1,  Bartłomiej Borek 1,  Karol Jedrzejczak 1,  Agnieszka Bartoszewicz 1,  Elżbieta Pluta 1,  Aleksandra Rymaszewska 1,  Magdalena Kania 1,  Tomasz Rejczak 1,  Sylwia Piasecka 1,  Michal Mlacki 1,  Marcin Mazurkiewicz 1,  Michał Piotrowicz 1,  Magdalena Salamon 1,  Agnieszka Zagozdzon 1,  Agnieszka Napiorkowska-Gromadzka 2,  Aneta Bartlomiejczak 2,  Witold Mozga 1,  Paweł Dobrzański 1,  Karolina Dzwonek 1,  Jakub Golab 1 3,  Marcin Nowotny 2,  Jacek Olczak 1,  Adam Golebiowski 1
Affiliations

Affiliations

  • 1 OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland.
  • 2 Structural Biology Center, International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw, Poland.
  • 3 Department of Immunology, Medical University of Warsaw, Nielubowicza 5, 02-097 Warsaw, Poland.
PMID: 33078933 DOI: 10.1021/acs.jmedchem.0c01179
Abstract

Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule 3 led to the identification of compound 9 (OATD-01), a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. OATD-01 given orally once daily in a range of doses between 30 and 100 mg/kg showed significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01 is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF.

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