Small molecules that mimic or antagonize actions of granulocyte colony-stimulating-factor (G-CSF)
Inventors
Sanchez-Ramos, Juan • Sava, Vasyl • Song, Shijie • Sebti, Said
Assignees
United States Government As Represented By Department Of Veterans • H Lee Moffitt Cancer Center and Research Institute Inc • US Department of Veterans Affairs • University of South Florida St Petersburg
Publication Number
US-10376495-B2
Publication Date
2019-08-13
Expiration Date
2037-11-22
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Abstract
Described herein are compound for the modulation of the G-CSF receptor. The compounds may act as agonists, antagonists, and/or mixed or partial agonists/antagonists of G-CSF. Further provided herein are methods of treating a condition, including, for example, a neurodegenerative disease, by administering a compound as detailed herein.
Core Innovation
The invention relates to compounds that modulate the granulocyte colony-stimulating factor (G-CSF) receptor, acting as agonists, antagonists, or mixed/partial agonists/antagonists, and methods of treating conditions such as neurodegenerative diseases by administering these compounds. These small molecules are designed according to specific chemical formulas and can mimic or antagonize the actions of G-CSF, providing effects such as stimulating the central nervous system G-CSF receptor and modulating related biological pathways.
G-CSF is known both as a hematopoietic growth factor and a neurotrophic factor affecting neural cells, but its clinical application as a neurotrophic factor is limited. The primary problems addressed include the high cost and complexity of manufacturing recombinant human G-CSF, peripheral actions that restrict safe dosing for brain disorders, and the absence of specific G-CSF receptor antagonists to selectively block peripheral effects while preserving neurotrophic effects in the brain.
The disclosed compounds overcome these problems by serving as small molecule mimetics of G-CSF that can selectively modulate G-CSF receptor activity. They may provide advantages such as stimulating neurons bearing the receptor, triggering intracellular signaling similar to G-CSF, and potentially blocking undesired peripheral effects like excessive leukocytosis. The invention includes methods of treating neurodegenerative diseases, stroke, traumatic brain injury, and related conditions by administering these compounds as alternatives or adjuncts to G-CSF.
Claims Coverage
The patent contains three independent claims focusing on methods of treating conditions by administering specific compounds described by chemical formulas, as well as methods of stimulating central nervous system G-CSF receptor in subjects.
Administration of compounds according to specified chemical formulas to treat conditions
The method comprises administering compounds according to Formula I, II, or III, characterized by distinct chemical substituents (R1-R10), to a subject in need to treat conditions including neurodegenerative disease, stroke, traumatic brain injury, impaired motor function, or impaired cognitive function.
Use of compounds to stimulate the central nervous system G-CSF receptor
The method includes administering compounds as defined in Formula I, II, or III to stimulate the central nervous system G-CSF receptor, with variations in specific chemical substituents as detailed in the formulas.
The claims protect methods of treating diverse neurological and cognitive impairments using specific structurally defined small molecule compounds that modulate G-CSF receptor activity, as well as methods specifically targeting stimulation of the CNS G-CSF receptor by administering these compounds.
Stated Advantages
The compounds provide an economical and potentially safer alternative to recombinant human G-CSF by being small molecules easier and cheaper to make.
They may selectively stimulate central nervous system G-CSF receptors to promote neurotrophic effects while minimizing peripheral side effects such as excessive leukocytosis.
Certain compounds can antagonize peripheral G-CSF receptor activity, blocking unwanted peripheral effects and thereby allowing higher or safer dosing for CNS indications.
Documented Applications
Treatment of neurodegenerative diseases including Alzheimer's Disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's Disease (PD), prion disease, motor neuron disease, Huntington's Disease, spinocerebellar ataxia, and spinal muscular atrophy.
Treatment of stroke.
Treatment of traumatic brain injury (TBI).
Improvement of impaired motor function.
Improvement of impaired cognitive function.
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