Treatment and prevention of pathological mitochondrial dysfunction in retinal degeneration and in photoreceptor injury.

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.

Pathogenic mitochondrial dysfunction and metabolic abnormalities.

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.

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs.

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.

Solid-phase analogue synthesis of caspase-3 inhibitors via palladium-catalyzed amination of 3-bromopyrazinones.

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.

Comparison between two classes of selective EP(3) antagonists and their biological activities.

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.

Novel pyrazinone mono-amides as potent and reversible caspase-3 inhibitors.

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.

Structure-activity relationship studies on ortho-substituted cinnamic acids, a new class of selective EP(3) antagonists.

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.

Solid phase synthesis of selective caspase-3 peptide inhibitors.

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.

Discovery of novel aspartyl ketone dipeptides as potent and selective caspase-3 inhibitors.

The discovery of a series of potent, selective and reversible dipeptidyl caspase-3 inhibitors are reported. The iterative discovery process of using combinatorial chemistry, parallel synthesis, moleculare modelling and structural biology will be discussed.