Acidic mammalian chitinase (AMCase; Mr=˜52.2 kD) is a secreted enzyme, typically found in the stomach, salivary gland, and lungs. Unique among mammalian enzymes in that it has an acidic pH optimum, the enzyme catalyzes the hydrolysis of artificial chitin-like substrates. It is induced during Th2 inflammation through an IL-13-dependent mechanism. Chitinases are believed to play a key role in the innate immunity to parasites and other infectious agents. When produced in a dysregulated fashion, the enzymes may also play an important role in the pathogenesis of allergy and/or asthma.
Asthma is a chronic inflammatory disease of the airways characterized by recurrent episodes of reversible airway obstruction and airway hyperresponsiveness (AHR). Typical clinical manifestations include shortness of breath, wheezing, coughing and chest tightness that can become life threatening or fatal. While existing therapies focus on reducing the symptomatic bronchospasm and pulmonary inflammation, there is a growing awareness of the role of long-term airway remodeling in the accelerated lung deterioration in asthmatics. Airway remodeling refers to a number of pathological features, including epithelial smooth muscle and myofibroblast hyperplasia and/or metaplasia, subepithelial fibrosis and matric deposition.
It is generally accepted that allergic asthma is initiated by an inappropriate inflammatory reaction to airborne allergens. The lungs of asthmatics demonstrate an intense infiltration of lymphocytes, mast cells and, especially, eosinophils. AMCase is prominently expressed in lungs from antigen-sensitized and challenged and IL-13-transgenic mice. AMCase mRNA is not readily detected in lung tissues from patients without known lung disease, but has been detected, histologically and morphometrically, in the epithelial cells and subepithelial cells in tissues from patients with asthma.
Preliminary published studies (Zhu Z, Zheng T, Homer R J, Kim Y K, Chen N Y, Cohn L, Hamid Q, and Elias J A. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science 304: 1678-1682, 2004; Matsumoto T, et al. Demethylallosamidin, a chitinase inhibitor, suppresses airway inflammation and hyperresponsiveness. Biochem Biophys Res Commun 390: 103-108, 2009) suggest that AMCase plays a role in the Th-2 driven inflammatory response in a murine model of allergic asthma. Th-1 responses do not seem to be involved. No therapeutic effect was observed in a mouse model that expresses Th-1, but not Th-2 (Fitz L J, et al. Acidic mammalian chitinase is not a critical target for allergic airway disease. Am J Respir Cell Mol Biol 46: 71-9, 2011). This result would be expected since Th-1 cells are primarily involved in host defense against pathogens.
Chitotriosidase 1 (CHIT1, Mr=˜52 kD or ˜39 kDa) is a chitinase expressed predominantly in the myeloid cells and lung epithelial cells as an innate immune mediator that digests the cell walls of chitin-containing eukaryotic pathogens. CHIT1 is a circulating enzyme, with both endochitinolytic and tranglycosylating activity. Besides its role in chitin recognition and innate immune response, CHIT1 is implicated in pathogenesis of fibrotic lung diseases. Lung fibrosis was significantly reduced in CHIT1 knockout mice in bleomycin-induced lung fibrosis animal model and it was suggested that this chitinase plays a role in tissue remodeling and fibrogenesis in the lung.
Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disorder refractory to current pharmacological therapies with a median survival of only 3-5 years following diagnosis. IPF is a devastating disease characterized by excessive matrix deposition that disrupts the normal architecture of the lung parenchyma. The key pathological features of IPF include fibroblastic foci, areas of epithelial cysts associated with the honeycombing appearance of the lung, and mild lymphoplasmacytic interstitial inflammation that is associated with areas of type II cell hyperplasia. The pathogenesis of each form of lung fibrosis remains poorly understood. They each result in a progressive loss of lung function with increasing dyspnea, and most forms ultimately result in mortality.
Poor prognosis of IPF patients generates a great need for novel targets that can be used as a therapeutic strategy to improve clinical outcomes in IPF, with CHIT1 among them. CHIT1 overexpression was shown in fibrotic Interstitial Lung Disease (ILD), including IPF (Bargagli W et al. Chitotriosidase activity in patients with interstitial lung diseases. Respir Med. 101(10):2176-81, 2007) and chronic obstructive pulmonary disease (COPD) (Letuve S et al. Lung chitinolytic activity and chitotriosidase are elevated in chronic obstructive pulmonary disease and contribute to lung inflammation. Am J Pathol. 176(2):638-49, 2010) characterized by inflammation and tissue remodeling and was interestingly shown to be potent amplifier of TGFβ signaling (Lee C G et al. Chitinase 1 is a biomarker for and therapeutic target in scleroderma-associated interstitial lung disease that augments TGF-β1 signaling. J Immunol. 189(5):2635-44, 2012). A study showed that CHIT1 activity was elevated in the BAL of IPF patients compare to controls suggesting it might be responsible for remodeling and tissue damage seen in the lung from IPF patients. As such, it is conceivable that CHIT1 could be involved in fibrogenesis of other ILD, such as systemic sclerosis (SSc), where patient group with lung involvement show high levels of circulating CHIT1 activity that correlate with disease severity.
Diseases, disorders, and conditions mediated by AMCase and CHIT1 are discussed in more detail below.
Substituted amino triazoles that inhibit AMCase and CHIT1 been described (see international patent application publication No. WO 2015/095701, and U.S. provisional patent application No. 62/094,446).
There is an ongoing need to investigate the inhibition of AMCase and CHIT1, and to discover treatments for conditions associated with elevated expression of AMCase or CHIT1, such as asthma and allergic responses or COPD and fibroproliferative disorders. In particular, there is a need for new molecular scaffolds that effectively inhibit AMCase and CHIT1, therefore, can act as therapeutic agents for the treatment of these conditions.