Important Compound Classes
Title
Isoxazole N-Linked Carbamoyl Cyclohexyl Acids as LPA Antagonists
Patent Application Number
WO 2019/126099
Publication Date
June 27, 2019
Priority Application
US 62/607,407
Priority Date
December 19, 2017
Inventors
Cheng, P. T. W.; Shi, Y.; Kaltenbach, R. F., III; Wang, Y.; Zhang, H.
Assignee Company
Bristol-Myers Squibb Company
Disease Area
Fibrosis such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis, arterial fibrosis, and systemic sclerosis and diseases that result from fibrosis (e.g., pulmonary fibrosis, idiopathic pulmonary fibrosis [IPF], hepatic fibrosis, and nonalcoholic steatohepatitis [NASH]).
Biological Target
Lysophosphatidic acid receptor 1 (LPA1)
Summary
The invention in this patent application is related to substituted isoxazole derivatives represented generally by either formula Ia or Ib. These compounds are inhibitors of lysophosphatidic acid (LPA) receptors, especially the LPA1 receptor, and may potentially be useful as treatment for different kinds of fibrosis and diseases resulting from fibrosis.
Lysophosphatidic acid (LPA) is an important
member of the lysophospholipids, which are membrane-derived bioactive
lipid mediators. While the name lysophosphatidic acid implies it is
a single molecular entity, the name actually refers to a collection
of endogenous structural analogues of 1-acyl-glycerol-3-phosphate
(structure below) in which the 1-hydroxy group is esterified with
saturated, monounsaturated, or polyunsaturated fatty acids of varied
lengths (mostly 16-, 18-, and 20-carbons long). The prefix “lyso”
refers here to the absence of a fatty acid ester at position 2 compared
to phosphatidic acids.
Lysophosphatidic acids are signaling bioactive lipids that affect a wide range of biological responses ranging from induction of cell survival, proliferation, differentiation, and migration as well as neurite retraction and gap junction closure. The different structural analogues of LPA can regulate various cellular signaling pathways by binding to and activating a family of 7-transmembrane domain G protein-coupled receptors (GPCR) known as LPA receptors. There are currently six identified LPA receptors designated as LPA1, LPA2, LPA3, LPA4, LPA5, and LPA6. LPAs have emerged recently as signaling molecules that are rapidly produced and released by activated cells, notably by platelets, to influence target cells by acting on specific cell-surface receptors.
LPAs are found normally in human plasma and serum
as well as human
bronchoalveolar lavage fluid (BALF) at very low levels. LPAs may be
produced by a de novo biosynthesis via the esterification of glycerol
3-phosphate at the 1-position with glycerol-3-phosphate acyltransferase-1
(GPAT1) as seen below.
LPAs may also be biosynthesized
by the degradation of more complex
phospholipids, for example, the hydrolysis of lysophosphatidylcholine
(LPC) by a plasma lysophospholipase D enzyme known as autotaxin (ATX)
or ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP 2) as
outlined below.
The enzyme autotaxin is responsible for elevating the concentration of LPA in blood and has been detected in platelet α-granules. There is evidence showing that ATX is upregulated by many tumor types and links ATX and LPA to tumor progression, metastasis, and resistance to chemotherapy or radiotherapy.
The body of knowledge about the biology of LPAs continues to expand as more and more cellular systems are being tested for LPA responsiveness. For example, in addition to the basic LPA functions of stimulating cell growth and proliferation, researchers have discovered that LPAs can promote cellular tension and cell-surface fibronectin binding, which are important events in wound repair and regeneration. Recent studies have linked LPAs to antiapoptotic activity and revealed that LPA acts as an agonist of peroxisome proliferator activated receptor-γ (PPARγ).
Fibrosis is a condition resulting from an uncontrolled tissue healing process leading to excessive accumulation and insufficient resorption of extracellular matrix (ECM) which ultimately results in end-organ failure. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic form of diffuse lung disease (DLD) that occurs mainly in older adults. The following findings have implicated LPA1 receptor in IPF:
LPA1 receptor is overexpressed in IPF patients.
LPA1 receptor knockout mice are immune against bleomycin-induced lung fibrosis.
A 26-week clinical trial showed that treatment of IPF patients with the LPA1 antagonist BMS-986020 has significantly reduced the patient’s rate of decline in forced vital capacity (FVC). [FVC is the measurement of the amount of air exhaled forcefully and quickly by a person after taking a deep breath.]
LPA pathway inhibitors such as LPA1 antagonists used to treat hepatocellular carcinoma in a rat model have behaved as chemopreventive antifibrotic agents.
Therefore, LPA1 receptor antagonists such as the compounds of formulas Ia and Ib described in this patent application may potentially be useful as a treatment for several forms of fibrosis including pulmonary fibrosis, hepatic fibrosis, renal fibrosis, arterial fibrosis, and systemic sclerosis. They may also be potentially useful in the treatment of several diseases that result from fibrosis such as Idiopathic Pulmonary Fibrosis [IPF], Nonalcoholic Steatohepatitis [NASH], chronic kidney disease, diabetic kidney disease, and systemic sclerosis.
Key Structures
The inventors have described the structures
and methods of synthesis of 65 examples of formula Ia including the
following representative examples:
Biological Assay
-
In Vitro Assay
LPA1 functional antagonist assay: using Chinese hamster ovary cells overexpressing human LPA1
-
In Vivo Assay
LPA challenge with plasma histamine evaluation
Biological Data
The biological data
obtained from testing
the above representative examples are included in the following table:
Recent Review Articles
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1.
Tigyi G. J.; Johnson L. R.; Lee S. C.; Norman D. D.; Szabo E.; Balogh A.; Thompson K.; Boler A.; McCool W. S.. J. Lipid Res. 2019, 60( (3), ), 464–474.
-
2.
Yang F.; Chen G.-X.. World J. Gastroenterol. 2018, 24( (36), ), 4132–4151.
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3.
Budd D. C.; Qian Y.. Future Med. Chem. 2013, 5( (16), ), 1935–1952.
The author declares no competing financial interest.