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Therapeutic Potential of Autotaxin Inhibitors in Treatment of Interstitial Lung Diseases.

Title. Novel Pyridazines Patent Application Number. WO 2020/089098 A1 Publication Date. 07 May 2020 Priority Application. EP 18203226.8 Priority Date. 29 October 2018 Inventors. Roth, G.; Bretschneider, T.; Kuttruff, A. Assignee Company. Boehringer Ingelheim International GMBH Disease Area. Interstitial Lung Diseases (ILDs) including idiopathic lung disease (IPF) and systemic sclerosis (SSc), chronic inflammation, autoimmune diseases Biological Target. Autotaxin (ATX) Summary.The invention in this patent application relates to pyridazine derivatives represented generally by formula I. These compounds are autotaxin inhibitors and may potentially be useful for the treatment and/or prevention of diseases and disorders mediated by autotaxin such as chronic inflammation, autoimmune diseases, fibrotic diseases, cancer progression, and tumor metastasis. Autotaxin (ATX), a.k.a. ectonucleotide pyrophosphatase/ phosphodiesterase 2 (ENPP2), is a lysophospholipase D enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA). LPA is a very strong bioactive lipid, which efficiently activates several downstream pathways via its interaction with six known G-protein-coupled receptors (GPCRs), namely, LPA Receptors 1−6, (LPAR1−6). Increased levels of ATX lead to overexpression of LPA. This, in turn, results in altering the LPA receptor expression and responses, which may affect a number of pathophysiological conditions related to autotaxin-lysophosphatidic acid (ATXLPA) signaling. ATX-LPA signaling has been implicated in several disorders including angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer progression, and tumor metastasis. For example, the effect of LPA on LPAR1 induces lung fibroblast migration, proliferation, and differentiation. It also modulates epithelial and endothelial barrier function and promotes lung epithelial cell apoptosis. Studies have shown that ATX inhibition, LPAR1 gene deletion, and selective LPAR1 antagonists were effective in preclinical models of fibrosis of the lung and skin. Interstitial lung diseases (ILDs) are characterized by inflammation and fibrosis of the interstitium, the tissue and space between the air sacs of the lung. An ILD may occur when an injury to the lungs triggers an abnormal healing response. ILDs include progressive fibrosing interstitial lung diseases (PFILDs) wherein the response to lung injury becomes progressive, self-sustaining, and independent of the original clinical association or trigger. Two of the major PF-ILDs are Idiopathic Pulmonary Fibrosis (IPF) and Systemic Sclerosis-ILD (SScILD). IPF is a serious chronic irreversible fibrotic lung disease that causes progressive fibrosis in the interstitium of the lung and leads to a decreased lung volume and progressive pulmonary insufficiency. Patients typically suffer from shortness of breath and a dry cough, and the disease may ultimately be fatal. Another hallmark of IPF is the development of a specific histopathologic pattern known as usual interstitial pneumonia (UIP). Researchers have observed increased levels of LPA in the bronchoalveolar lavage fluid and in the exhaled breath condensate as well as increased concentrations of ATX in fibrotic lung tissue of IPF patients. On the other hand, they observed a 2-fold increase in LPC in the serum of stable IPF patients. Systemic sclerosis (SSc) or scleroderma is an orphan autoimmune rheumatic disease with complex etiology and high unmet medical need. While the name scleroderma means “hard skin”, the disease may affect multiple organs in addition to skin. SSc is a heterogenic disease characterized by extensive fibrosis (production and accumulation of collagen), vasculopathy (disorder of the blood vessels), and autoantibodies against various cellular antigens. Some of the disease early clinical signs include Raynaud’s phenomenon (a condition resulting from low blood to the hands and feet) and gastro-esophageal reflux. Patients may also suffer from inflammatory skin disease, puffy and swollen fingers, musculoskeletal inflammation, and fatigue. The deposition of excess collagen in the skin causes patients’