Acidic mammalian chitinase (AMCase) and chitotriosidase-1 (CHIT1) are two enzymatically active proteins produced by mammals capable of cleaving the glycosidic bond in chitin. Based on the clinical findings and animal model studies, involvement of chitinases has been suggested in several respiratory system diseases including asthma, COPD, and idiopathic pulmonary fibrosis. Exploration of structure–activity relationships within the series of 1-(3-amino-1H-1,2,4-triazol-5-yl)-piperidin-4-amines, which was earlier identified as a scaffold of potent AMCase inhibitors, led us to discover highly active dual (i.e., AMCase and CHIT1) inhibitors with very good pharmacokinetic properties. Among them, compound 30 was shown to reduce the total number of cells in bronchoalveolar lavage fluid of mice challenged with house dust mite extract after oral administration (50 mg/kg, qd). In addition, affinity toward the hERG potassium channel of compound 30 was significantly reduced when compared to the earlier reported chitinase inhibitors.

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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The characteristic feature of the title molecule, C 16 H 23 NO 4 , is the syn configuration of the partially double amide C-N bond [C-N-C-O torsion angle = À14.8 (2) ]. The crystal packing is determined by intermolecular O-HÁ Á ÁO and N-HÁ Á ÁO hydrogen bonds, which link the molecules into a double-chain structure extending along [010].

Depletion of arginine represents an important mechanism of immunosuppression, and high plasma and tumor arginase (ARG) activity has been demonstrated in patients with a wide spectrum of cancers and correlated with a poor prognosis. Low arginine levels inhibit proliferation and activation of cytotoxic T and NK cells. Preclinical and clinical studies show that simultaneous interference with multiple mechanisms of immunosuppression results in a strongly improved antitumor efficacy. In this context, we have developed OAT-1746, a novel, potent, and selective small-molecule inhibitor of ARG1 and ARG2 with profound antitumor efficacy as a monotherapy and in combinations with gemcitabine and PD-L1 inhibitor. The IC50 of OAT-1746 was determined against the recombinant human and murine ARG1 and ARG2. Cellular activity was evaluated in M2-polarized, bone marrow-derived murine macrophages, and CHO cells transfected with human ARG1 or ARG2. The in vivo antitumor efficacy of OAT-1746 was evaluated in syngeneic mouse models and in an orthotopic C6 rat glioma model after oral administration. In the rat model, C6 glioma cells were implanted by stereotactic intracranial inoculation and the tumor size was measured by bioluminescence in vivo imaging or immunohistochemistry. Quantitative real-time PCR was used to determine inflammatory markers. The tumor arginase activity was assessed using the urea detection assay. L-Arginine and drug levels in plasma and tumor were evaluated by LC/MS method. We have developed potent, selective, orally active inhibitors of ARG1 and ARG2. The clinical candidate, OAT-1746, has IC50=32 nM and 50 nM against human ARG1 and ARG2, respectively, and a potent cellular activity (M2 macrophages IC50=32 nM, CHO-K1 hARG1 IC50=55 nM). In vivo, OAT-1746 showed good pharmacologic properties and demonstrated significant antitumor efficacy as a monotherapy in 4 tumor models: B16 (melanoma), LLC (lung carcinoma), CT26 (CRC), and C6 glioma with TGI=34-53%. The antitumor efficacy correlated with sustained pharmacodynamic (PD) effects: suppression of tumor arginase activity and 3-6 fold increases in plasma and tumor arginine concentrations. Induction of inflammatory markers in tumors confirmed reversal of immunosuppression. Combinations of OAT-1746 with PD-L1 checkpoint inhibitor and gemcitabine showed increased efficacy. Administration of OAT-1746 with anti-PD-L1 antibody resulted in a “controlled” tumor growth with 55% of tumors remaining under 500 mm3 at day 24 versus 36% for PD-L1 monotherapy. Full regression was observed in 20% of the animals treated in combination with gemcitabine in comparison to 0% for monotherapy. OAT-1746 also demonstrated efficacy and PD effects in the orthotopic model of GBM, confirming its ability to cross the blood-brain barrier. Together these results support the clinical development of OAT-1746 for cancer therapy. Citation Format: Paulina Seweryna Stanczak, Marcin Mikolaj Grzybowski, Paulina Wolska, Anna Maria Zdziarska, Marcin Mazurkiewicz, Paulina Pilanc, Anna Gieryng, Bozena Kaminska, Anna Gzik, Marek Dziegielewski, Karol Jedrzejczak, Bartlomiej Borek, Roman Blaszczyk, Adam Golebiowski, Pawel Dobrzanski, Karolina Dzwonek. Development of OAT-1746, a novel arginase 1 and 2 inhibitor for cancer immunotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B003.