R. W. Sabnis
Jun 8, 2021
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Journal
ACS medicinal chemistry letters
Abstract
Title. N-Methyl, N-(6-(Methoxy)pyridazin-3-yl)amine Derivatives as Autotaxin (ATX) Modulators for the Treatment of Inflammatory Airway or Fibrotic Diseases Patent Publication Number. WO 2021/013830 A1 Publication Date. January 28, 2021 Priority Application. EP 19187617.6 Priority Date. July 22, 2019 Inventors. Kuttruff, C. A.; Bretschneider, T.; Godbout, C.; Koolman, H. F.; Martyres, D.; Roth, G. J. Assignee Company. Boehringer Ingelheim International GmbH, Germany Disease Area. Inflammatory airway or fibrotic diseases Biological Target. Autotaxin (ATX) Summary. Autotaxin (ATX, ENPP2) is a secreted enzyme responsible for hydrolyzing lysophosphatidylcholine (LPC) to the bioactive lipid lysophosphatidic acid (LPA) through its lysophospholipase D activity. In turn, LPA exerts its effects by interacting with six GPCRs (LPA Receptors 1−6, LPAR1−6). ATX-LPA signaling has been implicated for example in angiogenesis, chronic inflammation, autoimmune diseases, fibrotic diseases, cancer progression, and tumor metastasis. For example, LPA, acting on LPAR1, induces lung fibroblast migration, proliferation, and differentiation; modulates epithelial and endothelial barrier function and promotes lung epithelial cell apoptosis. ATX inhibition, LPAR1 gene deletion and selective LPAR1 antagonists have been shown to be effective in preclinical models of fibrosis of the lung and skin. In idiopathic pulmonary fibrosis (IPF) patients, LPA levels in bronchoalveolar lavage fluid are increased. Increased ATX levels, increased LPA levels, altered LPA receptor expression, and altered responses to LPA may affect a number of pathophysiological conditions related to ATX-LPA signaling. Intestinal lung diseases (ILDs) are characterized by inflammation and fibrosis of the interstitium, tissue, and space between the air sacs of the lung. Systemic sclerosis (SSc), also called as scleroderma, is an immune-mediated rheumatic disease of complex etiology. It is a multiorgan, heterogenic disease characterized by extensive fibrosis, vasculopathy, and autoantibodies against various cellular antigens with high mortality. The present application describes a series of novel pyridazines as autotaxin (ATX) inhibitors for the treatment of inflammatory airway or fibrotic diseases. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment. Definitions. A = pyridyl substituted with one or more members of the group consisting of fluoro and F1−7-fluoro-C1−3alkyl; E = phenyl and pyridyl optionally substituted with one or more members of the group consisting of fluoro and F1−7-fluoroC1−3-alkyl;