Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
Add more filters










Database
Language
Publication year range
1.
Biochem Pharmacol ; 203: 115168, 2022 09.
Article in English | MEDLINE | ID: mdl-35835206

ABSTRACT

Pathological deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and age-related chronic diseases, including those of genetic origin. Several of these diseases are rare, typically defined in the United States as an illness affecting fewer than 200,000 people in the U.S. population, or about one in 1600 individuals. Vision impairment due to mitochondrial dysfunction in the eye is a prominent feature evident in numerous primary mitochondrial diseases and is common to the pathophysiology of many of the familiar ophthalmic disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma and retinopathy of prematurity - a collection of syndromes, diseases and disorders with significant unmet medical needs. Focusing on metabolic mitochondrial pathway mechanisms, including the possible roles of cuproptosis and ferroptosis in retinal mitochondrial dysfunction, we shed light on the potential of α-lipoyl-L-carnitine in treating eye diseases. α-Lipoyl-L-carnitine is a bioavailable mitochondria-targeting lipoic acid prodrug that has shown potential in protecting against retinal degeneration and photoreceptor cell loss in ophthalmic indications.


Subject(s)
Retinal Degeneration , Carnitine/metabolism , Humans , Infant, Newborn , Mitochondria/metabolism , Photoreceptor Cells/metabolism , Photoreceptor Cells/pathology , Retina/metabolism , Retinal Degeneration/drug therapy , Retinal Degeneration/metabolism , Retinal Degeneration/prevention & control
2.
Biochem Pharmacol ; 193: 114809, 2021 11.
Article in English | MEDLINE | ID: mdl-34673016

ABSTRACT

Herein we trace links between biochemical pathways, pathogenesis, and metabolic diseases to set the stage for new therapeutic advances. Cellular and acellular microorganisms including bacteria and viruses are primary pathogenic drivers that cause disease. Missing from this statement are subcellular compartments, importantly mitochondria, which can be pathogenic by themselves, also serving as key metabolic disease intermediaries. The breakdown of food molecules provides chemical energy to power cellular processes, with mitochondria as powerhouses and ATP as the principal energy carrying molecule. Most animal cell ATP is produced by mitochondrial synthase; its central role in metabolism has been known for >80 years. Metabolic disorders involving many organ systems are prevalent in all age groups. Progressive pathogenic mitochondrial dysfunction is a hallmark of genetic mitochondrial diseases, the most common phenotypic expression of inherited metabolic disorders. Confluent genetic, metabolic, and mitochondrial axes surface in diabetes, heart failure, neurodegenerative disease, and even in the ongoing coronavirus pandemic.


Subject(s)
COVID-19/metabolism , Metabolic Diseases/metabolism , Mitochondria/metabolism , Mitochondrial Diseases/metabolism , Neurodegenerative Diseases/metabolism , Animals , COVID-19/therapy , Diet, Healthy , Energy Metabolism/physiology , Humans , Metabolic Diseases/therapy , Mitochondrial Diseases/therapy , Neurodegenerative Diseases/therapy , Oxidative Stress/physiology
3.
Biores Open Access ; 9(1): 94-105, 2020.
Article in English | MEDLINE | ID: mdl-32257625

ABSTRACT

In this review we outline a rationale for identifying neuroprotectants aimed at inducing endogenous Klotho activity and expression, which is epigenetic action, by definition. Such an approach should promote remyelination and/or stimulate myelin repair by acting on mitochondrial function, thereby heralding a life-saving path forward for patients suffering from neuroinflammatory diseases. Disorders of myelin in the nervous system damage the transmission of signals, resulting in loss of vision, motion, sensation, and other functions depending on the affected nerves, currently with no effective treatment. Klotho genes and their single-pass transmembrane Klotho proteins are powerful governors of the threads of life and death, true to the origin of their name, Fates, in Greek mythology. Among its many important functions, Klotho is an obligatory co-receptor that binds, activates, and/or potentiates critical fibroblast growth factor activity. Since the discovery of Klotho a little over two decades ago, it has become ever more apparent that when Klotho pathways go awry, oxidative stress and mitochondrial dysfunction take over, and age-related chronic disorders are likely to follow. The physiological consequences can be wide ranging, potentially wreaking havoc on the brain, eye, kidney, muscle, and more. Central nervous system disorders, neurodegenerative in nature, and especially those affecting the myelin sheath, represent worthy targets for advancing therapies that act upon Klotho pathways. Current drugs for these diseases, even therapeutics that are disease modifying rather than treating only the symptoms, leave much room for improvement. It is thus no wonder that this topic has caught the attention of biomedical researchers around the world.

4.
Bioorg Med Chem Lett ; 17(6): 1671-4, 2007 Mar 15.
Article in English | MEDLINE | ID: mdl-17251019

ABSTRACT

Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact on the treatment of several degenerative diseases. Here we report the synthesis of reversible inhibitors via a solid-support palladium-catalyzed amination of 3-bromopyrazinones and the discovery of a pan-caspase reversible inhibitor.


Subject(s)
Caspase Inhibitors , Palladium/chemistry , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Amination , Catalysis , Cell Line , Chromatography, High Pressure Liquid , Humans , Indicators and Reagents , Mass Spectrometry , Recombinant Proteins/chemistry , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 16(21): 5639-42, 2006 Nov 01.
Article in English | MEDLINE | ID: mdl-16931013

ABSTRACT

Two different series of very potent and selective EP(3) antagonists have been reported: a novel series of ortho-substituted cinnamic acids [Belley, M., Gallant, M., Roy, B., Houde, K., Lachance, N., Labelle, M., Trimble, L., Chauret, N., Li, C., Sawyer, N., Tremblay, N., Lamontagne, S., Carrière, M.-C., Denis, D., Greig, G. M., Slipetz, D., Metters, K. M., Gordon, R., Chan, C. C., Zamboni, R. J. Bioorg. Med. Chem. Lett.2005, 15, 527] and the acylsulfonamides of ortho-(arylmethyl)cinnamates. [(a) Juteau, H., Gareau, Y., Labelle, M., Sturino, C. F., Sawyer, N., Tremblay, N., Lamontagne, S., Carrière, M.-C., Denis, D., Metters, K. M. Bioorg. Med. Chem. 2001, 9, 1977; (b) Juteau, H., Gareau, Y., Labelle, M., Lamontagne, S., Tremblay, N., Carrière, M.-C., Denis, D., Sawyer, N., Metters, K. M. Bioorg. Med. Chem. Lett.2001, 11, 747] The structural differences between the two series, along with their biological activity in vivo, in vitro, and metabolism, are analyzed. Some of those compounds, including hybrids containing the best structural features of both series, possess K(i) as low as 0.6 nM on the EP(3) receptor.


Subject(s)
Cinnamates/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Sulfonamides/pharmacology , Cinnamates/chemistry , Humans , Sulfonamides/chemistry
6.
Bioorg Med Chem Lett ; 15(4): 1173-80, 2005 Feb 15.
Article in English | MEDLINE | ID: mdl-15686936

ABSTRACT

The iterative process for the discovery of a series of pyrazinone mono-amides as potent, selective and reversible non-peptide caspase-3 inhibitors (e.g., M826 and M867) is reported. These compounds display potent anti apoptotic activities in a number of cell based systems in vitro as well as in several animal models in vivo.


Subject(s)
Amides/chemical synthesis , Caspase Inhibitors , Amides/pharmacology , Animals , Apoptosis/drug effects , Caspase 3 , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Leukocytes/drug effects , Mice , Neurons/drug effects , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Rats , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 15(3): 527-30, 2005 Feb 01.
Article in English | MEDLINE | ID: mdl-15664806

ABSTRACT

A series of novel ortho-substituted cinnamic acids have been synthesized, and their binding activity and selectivity on the four prostaglandin E(2) receptors evaluated. Many of them are very potent and selective EP(3) antagonists (K(i) 3-10 nM), while compound 9 is a very good and selective EP(2) agonist (K(i) 8 nM). The biological profile of the EP(2) agonist 9 in vivo and the metabolic profile of selected EP(3) antagonists are also reported.


Subject(s)
Cinnamates/chemical synthesis , Cinnamates/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Cell Line , Cinnamates/metabolism , Cyclic AMP/biosynthesis , Humans , Pharmacokinetics , Protein Binding , Receptors, Prostaglandin E, EP2 Subtype , Receptors, Prostaglandin E, EP3 Subtype , Structure-Activity Relationship
8.
Bioorg Med Chem ; 12(5): 845-51, 2004 Mar 01.
Article in English | MEDLINE | ID: mdl-14980595

ABSTRACT

A robust method for the solid phase synthesis of a series of selective caspase-3 peptide inhibitors is described. The inhibitors can be obtained after cleavage from the solid support without further purification.


Subject(s)
Caspase Inhibitors , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Caspase 3 , Cell Line , Cell Survival/drug effects , Combinatorial Chemistry Techniques , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50
SELECTION OF CITATIONS
SEARCH DETAIL
...