Important Compound Classes
Title
2-Aminoaryl-5-aryloxazole Analogs for the Treatment of Neurovegetative Diseases
Patent Application Number
WO 2019/164996 A1
Publication Date
August 29, 2019
Priority Application
US 62/633,577
Priority Date
February 21, 2018
Inventors
Suto, M, J.; Mathew, B.; Cowell, R.; Augelli-Szafran, C. E.
Assignee Company
Southern Research Institute; 2000 Ninth Avenue South, Birmingham, AL 35205 (US).
Disease Area
Neurodegenerative, amyotrophic lateral sclerosis, Alzheimer’s and Cardiovascular diseases
Biological Target
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB).
Summary
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that is rare, progressive but ultimately fatal, and affects the upper and lower motor neurons of the central nervous system (CNS). An estimate of 13 persons per day are diagnosed with ALS in the US, and 90–95% of ALS cases is of the sporadic type with no family history of the disease (https://www.rightdiagnosis.com/a/amyotrophic_lateral_sclerosis/stats.htm, accessed, 11/02/2019). Worldwide, ALS affects 1–1.8/100,000 individuals, and the number of cases is projected to increase in aging populations. Genetic alterations have been found in both groups (sporadic and familiar types) with more than 35 major ALS related genes and approximately 160 alterations of these genes. In general, multiple genes have been identified that eventually lead to ALS and superoxide dismutase 1 (SOD1) mutations accounting for about 20% of familiar ALS and 2% of all ALS cases.
The symptoms of the disease are first observed at the focal site of onset and process by deposition of insoluble aggregated proteins in the cytoplasm of affected cells. ALS causes irreversible degeneration of the upper (cortical) and lower (brain stem and spinal cord) motor neurons (MNs), which may be accompanied by paralysis of voluntary muscle leading to respiratory failure and death within 5 years from diagnosis. The pathological signature for ALS condition has been identified as hyperphosphorylated and ubiquitinated pathological forms of both full-length and proteolytic cleavage fragments of TDP-43. The pathogenesis involves abnormalities of the cytosolic enzyme CuZn superoxide dismutase (SOD1). SOD1 is an antioxidant enzyme that catalyzes the dismutation of superoxide radicals, which exhibits physical characteristics that increase the likelihood of unfolding, misfolding, aggregation, polymerization, loss of function, and possibly toxic gain of function. Multiple studies have revealed that many strains of mutant SOD1 and oxidized SOD1 can be toxic in cells and in neuronal lines. Understanding of the physicochemical properties of the human wild-type SOD1 and its various mutations has continually improved; however, how SOD1 mutations actually cause motor neuron degeneration remains unclear. The roles of misfolded and aggregated SOD1 in ALS are mirrored in other neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases. While there is general consensus that non-natively folded SOD1 is toxic, however, the roles of SOD1 aggregation in ALS disease pathogenesis remain controversial.
In contrast, superoxide dismutase 2 (SOD2), a key antioxidant enzyme in the mitochondria, can reduce reactive oxygen species production and protect cells against oxidative stress. SOD2 is upregulated during the spread of ALS, and expression in the brain is uniquely controlled by the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 activation. Furthermore, neuronal noncytokine-dependent p50/p65 nuclear factor-κB activation has been shown to exert neuroprotective actions. The NF-κB proteins comprise a family of structurally related eukaryotic transcription factors that regulate the expression of genes influencing a broad range of normal cellular and organismal processes, including innate and adaptive immunity, B-cell development, inflammation, stress responses, and lymphoid organogenesis. Consequently, SOD2 and neuronal activation of NF-κB could represent a viable neuroprotective shield and could be targeted to devise novel approaches for the treatment of many neurodegenerative diseases.
This Patent Highlight contains compounds and compositions for use in the prevention and treatment of neurological disorders such as ALS, Alzheimer’s disease, Parkinson’s disease, spinal muscular atrophy, traumatic brain injury, and attention deficit and hyperactivity disorder (ADHD).
Definitions
R1 = H, C1–C4 alkyl;
R2 = −C(F)=CHCH3, −C(CN)=NOCH3;
Ar1 = Ar2 = monocyclic aryl and pyridinyl, and substituted with 0, 1, 2, or 3 groups independently selected from halogen, −CN, −NH2, −OH, C1–C4 alkyl, and so forth.
Key Structures
Biological Assay
High throughput assay for NF-κB reporter activity, quantitative RT-PCR for manganese superoxide dismutase, and in vivo pharmacology.
Biological Data
Compound 40 was orally bioavailable
(16%) and had solubility of 56 μM and t1/2 in HLM and MLM of 260 and 100 min, respectively. Congenic
SOD1 G93A mice were dosed with 50 mg/kg of compounds 1 and 2 via i.p. injection to rule out toxicity and showed
substantial plasma and brain levels within 30 min. The compounds in
this Patent Highlight are capable of activating NF-κB signaling
and are exemplified in the Table below.
Recent Review Articles
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Vijayakumar U. G.; Milla V.; Cynthia S. M. Y.; Bjourson A. J.; Duddy W.; Duguez S. M.. Front. Neurol. 2019, 10400.
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Logroscino G.; Piccininni M.; Logroscino G.; Piccininni M.. J. Neuroepidemiology 2019, 52, 93.
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Yuan J.; Zhang Y.; Wang X.; Liu X.; Botchway B. O. A.; Tan X.. Cell. Mol. Neurobiol. 2019, 39, 569.
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Kabacaoglu D.; Ai J.; Algul H.; Ruess D. A.. Cancers 2019, 11, 937.
The author declares no competing financial interest.