Journal of Medicinal Chemistry p. 15527 - 15540 (2020)
Update date:2022-08-11
Topics:
Koralewski, Robert
Dymek, Barbara
Mazur, Marzena
Sklepkiewicz, Piotr
Olejniczak, Sylwia
Czestkowski, Wojciech
Matyszewski, Krzysztof
Andryianau, Gleb
Niedziejko, Piotr
Kowalski, Michal
Gruza, Mariusz
Borek, Bart?omiej
Jedrzejczak, Karol
Bartoszewicz, Agnieszka
Pluta, El?bieta
Rymaszewska, Aleksandra
Kania, Magdalena
Rejczak, Tomasz
Piasecka, Sylwia
Mlacki, Michal
Mazurkiewicz, Marcin
Piotrowicz, Micha?
Salamon, Magdalena
Zagozdzon, Agnieszka
Napiorkowska-Gromadzka, Agnieszka
Bartlomiejczak, Aneta
Mozga, Witold
Dobrzański, Pawe?
Dzwonek, Karolina
Golab, Jakub
Nowotny, Marcin
Olczak, Jacek
Golebiowski, Adam
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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