CN-114980880-B - Mitochondrial targeting antioxidants

Abstract

The present invention relates to compounds having a lipid affinity (e.g., -0.75 or less log p) of less than 15% by weight of the compound for targeting mitochondria to reduce, inhibit or prevent mitochondrial reactive oxygen species formation and for treating or preventing pathological conditions associated with elevated levels of mitochondrial reactive oxygen species, as well as for non-therapeutic uses, such as enhancing athletic performance and reducing, inhibiting or preventing mitochondrial reactive oxygen species formation during exercise, resulting in maintenance of muscle strength and/or reduction of muscle fatigue and related methods. The invention also relates to extracts and compositions comprising compounds having a lipid affinity of less than 15% (e.g., -0.75 or less log p) for the same use. The preferred compound is sinapine, optionally in the form of an extract obtained or obtainable from Brassica napus (Brassica napus).

Inventors

• D. Burgobra
• M. LAGUERRE
• M. Turnon
• J. Fauconier
• S. Biltik
• P.E.R. Fonka-Belton
• C Le Boer
• O. Cazorla

Assignees

• 奇华顿股份有限公司
• 阿维尼翁大学
• 蒙彼利埃大学
• 国家科研中心
• 国家健康与医学研究院

Dates

Publication Date

20260505

Application Date

20201106

Priority Date

20191107

Claims (7)

1. 1. The use of a compound of formula (IA) or a pharmaceutically acceptable salt thereof for the manufacture of a product for enhancing muscle recovery during and/or after exercise, (IA) Wherein W - is a counter ion, wherein the compound has a lipid affinity of less than 15%, wherein the lipid affinity is defined as a partition coefficient log p of the compound between water and octanol of-0.75 or less.
2. 2. Use according to claim 1, wherein the compound of formula (IA) is in the form of an extract obtained or obtainable from a cruciferous (Brassicaceae family) plant.
3. 3. Use according to any one of claims 1 to 2, wherein the compound of formula (IA) is sinapine or a pharmaceutically acceptable salt thereof.
4. 4. Use according to claim 1, wherein the compound of formula (IA) is provided in the form of a nutraceutical formulation, a nutritional supplement, a sports supplement, a pharmaceutical or veterinary formulation, a cosmetic formulation.
5. 5. The use according to claim 4, wherein the nutraceutical, nutritional supplement, exercise supplement, pharmaceutical or veterinary formulation, cosmetic formulation comprises a compound of formula (IA) or an extract obtained or obtainable from crucifers in an amount of about 0.5% to about 100% by weight.
6. 6. The use according to claim 4 or 5, wherein the nutraceutical formulation, nutritional supplement, exercise supplement, pharmaceutical or veterinary formulation, cosmetic formulation further comprises a pharmaceutically or veterinarily acceptable excipient or food acceptable ingredient.
7. 7. Use according to claim 6, wherein the food product is a functional food product.

Description

Mitochondrial targeting antioxidants The present invention relates to compounds having a lipid affinity (e.g., -0.75 or less log p) of less than 15% by weight of the compound for targeting mitochondria to reduce, inhibit or prevent mitochondrial reactive oxygen species formation, and for treating or preventing pathological conditions associated with elevated levels of mitochondrial reactive oxygen species, and for non-therapeutic uses, such as enhancing exercise (sports) performance and reducing, inhibiting or preventing mitochondrial reactive oxygen species formation during exercise (exercise), thereby maintaining muscle strength and/or reducing muscle fatigue and related methods. The invention also relates to extracts and compositions comprising compounds having a lipid affinity of less than 15% (e.g., -0.75 or less log p) for the same use. The listing or discussion of a prior-published reference in this specification should not necessarily be taken as an acknowledgement that the reference was part of the state of the art or was common general knowledge. Mitochondria are intracellular organelles responsible for energy metabolism and are present in all eukaryotic cells. However, they are considered to be the main intracellular source of Reactive Oxygen Species (ROS). Mitochondrial ROS (mtROS) are Reactive Oxygen Species (ROS) produced by mitochondria and are referred to as "mitochondrial" as long as they are located in mitochondria. For example, H 2O2, hydroxyl radicals and superoxide anions located in mitochondria, which are especially damaging to nerve and muscle tissue with high energy requirements. The imbalance between ROS and antioxidant defenses can interfere with the normal redox state of the cell and cause a pathological condition known as oxidative stress. Since 1966 it was found that mitochondrial production ROS (mtROS) (Jensen PK. Antimycin-insensitive oxidation of succinate and reduced nicotinamide-adenine dinucleotide in electron-transport particles. II. Steroid effects. Biochim. Biophys. Acta 1966,122,167-174), of these partially reduced forms of oxygen is associated with an increasing number of pathological conditions, in particular when present in excess compared to antioxidants. For example, neurodegenerative diseases (Kausar et al ,The role of mitochondria in reactive oxygen species generation and its implications for neurodegenerative diseases. Cell 2018,7,274-293), such as Parkinson's disease), Alzheimer's disease and Huntington's disease, diabetes and insulin resistance (Bonnard et al ,Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Invest. 2008,118,789-800;Bugger and Abel Mitochondria in the diabetic heart, cardiova, res, 2010,88,229-240), and cancer, in which mitochondrial ROS amplify the tumorigenic phenotype and accelerate the accumulation of additional mutations leading to metastatic behavior (Sabharwal and Schumacker,Mitochondrial ROS in cancer：initiators,amplifiers or an Achilles' heel? Nat. Rev. Cancer volume 2014,14,709-721); inflammation and ischemia-reperfusion (Loor et al ,Mitochondrial oxidant stress triggers cell death in simulated ischemia-reperfusion. Biochim. Biophys. Acta-Mol. Cell Res. 2011,1813,1382-1394;Chouchani et al, A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury), heart failure (Ide et al ,Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ. Res. 1999,85,357-363,Andre et al ,Subendocardial increase in reactive oxygen species production affects regional contractile function in ischemic heart failure. Antiox. Redox Signal. 2013,18,1009-1020;Brown et al ,Mitochondrial function as a therapeutic target in heart failure. Nat. Rev. Cardiol. 2017,14,238-250); peripheral arterial disease (Hart et al ,Increased skeletal muscle mitochondrial free radical production in peripheral arterial disease despite preserved mitochondrial respiratory capacity. Exp. Physiol. 2018,103,838-850); hyperglycemia (Nishikawa et al ,Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000,404,787-790); chronic obstructive pulmonary disease (Wiegman et al ,Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 2015,136,769-780;Puente-Maestu et al ,Abnormal mitochondrial function in locomotor and respiratory muscles of COPD patients. Eur. Respir J. 2009,33,1045-1052;Puente-Maestu et al ,Abnormal transition pore kinetics and cytochrome C release in muscle mitochondria of patients with chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol. 2009,40,746-750;Puente-Maestu et al ,Site of mitochondrial reactive oxygen species production in skeletal muscle of chronic obstructive pulmonary disease and its rela