Important Compound Classes
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 (ATX-LPA) 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 (PF-ILDs) 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 (SSc-ILD).
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’ skin to be thick and tough. Some SSc patients may develop lung fibrosis, pulmonary arterial hypertension, renal failure, or gastrointestinal complications. In addition, nearly every SSc patient displays an abnormal level of autoimmune antibodies to the nucleus of patient’s own cells (antinuclear antibodies or ANA). The most frequent complications that cause mortality in SSc patients are interstitial lung diseases (ILD) and pulmonary arterial hypertension (PAH).
There are two major forms of SSc disease based on the extent and areas affected in patients:
limited cutaneous scleroderma: slower to develop and less widespread form of the disease. Its effects are usually limited to the fingers, hands, legs and face.
diffuse cutaneous scleroderma: faster to develop and spreads to more skin areas. Patients are also at a higher risk of developing fibrous hardening of internal organs such as kidneys, heart, lungs, and gastrointestinal tract.
Overexpression of ATX and LPA has been detected in patients with chronic inflammatory diseases, particularly in idiopathic pulmonary fibrosis (IPF), autoimmune diseases, rheumatoid arthritis, tumor progression, and metastasis. Studies have suggested a role for ATX in pathogenesis of IPF. These findings were driving factors to initiate extensive dedicated research to identify and develop ATX inhibitors as potential treatment for many of the above-mentioned diseases.
While several ATX inhibitors were identified and tested, there is still a need for the discovery of new more potent ones. The inventors have stated that the disclosed pyridazine derivatives of formula I, described in this patent application, are superior ATX inhibitors compared to previously disclosed inhibitors based on meeting the following three requirements:
inhibition of ATX,
inhibition of ATX in human whole blood,
ability to reduce plasma concentration levels of LPA in vivo over several hours
Thus, the compounds of formula I in this patent application have demonstrated high in vivo ATX inhibition target and may potentially display good efficacy in human testing.
Key Structures
The inventors described the structures
and methods of synthesis of 11 examples of formula I including the
following examples.
Biological Assay
Assay A: Biochemical ATX assay
Assay B: Whole-blood ATX assay
Assay C: Measurement of the reduction of the plasma concentration levels of LPA in vivo over several hours
Biological Data
The data obtained from testing the
above representative examples using assays A, B, or C are displayed
in the following table
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The author declares no competing financial interest.