Acidic mammalian chitinase (AMCase) and chitotriosidase (CHIT1) are enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases. Significantly elevated chitinolytic activity was demonstrated in asthma, chronic obstructive pulmonary disease (COPD) and interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) and sarcoidosis. Herein, we describe our studies on targeting chitinases with small molecules as a potential therapy for pulmonary diseases. In the course of our program 2500 compounds have been designed and synthesized, resulting in OAT-870 as our advanced lead compound. Further optimization of drug-like properties and selectivity of OAT-870 yielded a clinical candidate – OAT-889/OATD-01. The compound bears an additional methyl group at the morpholine ring, which abrogated undesired off-target activity towards dopamine transporter (DAT). OATD-01 is a nanomolar inhibitor of AMCase and CHIT1 with optimal pharmacokinetic profile in rodents and dogs. In addition to anti-inflammatory efficacy in asthma models, interestingly OATD-01 exhibited anti-fibrotic effects in a chronic HDM-induced airway remodelling model and in a bleomycin-induced pulmonary fibrosis model in mice. These data indicate that inhibition of chitinases might represent a novel therapeutic approach for pulmonary diseases as well as several fibrotic pathologies. Moreover, OATD-01 is the first-in-class chitinase inhibitor to have entered clinical trials (currently in phase 1b).

OATD-01: Dual hAMCase and hCHIT inhibitor as a potential therapeutic agent for treatment of pulmonary diseases

2019 Fall National Meeting

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