Important Compound Classes
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 2021/013833 A1
Publication Date
January 28, 2021
Priority Application
EP 19187616.8
Priority Date
July 22, 2019
Inventors
Kuttruff, C. A.; Godbout, C.; Koolman, H. F.; 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, the 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 and 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-C1–3-alkyl;
E = phenyl and pyridyl optionally substituted with one or two members of the group consisting of fluoro and C1–3-alkyl;
R3 = R4(O)C– and R5(O)C(CH3)N–;
R4 = methyl; R5 = methyl; and
L and M form together with the carbon to which they are joined, a cyclopropyl ring.
Key Structures
Biological Assay
The human ATX LPA biochemical assay was performed. The compounds described in this application were tested for their ability to inhibit ATX. The ATX IC50 (nM) are shown in the following Table.
Biological Data
The Table below shows representative
compounds were tested for ATX inhibition. The biological data obtained
from testing representative examples are listed in the following Table.
Claims
Total claims: 10
Compound claims: 9
Pharmaceutical composition claims: 1
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The author declares no competing financial interest.