Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease in which the motor neuron circuitry displays progressive degeneration, affecting mostly the motor neurons in the brain and in the spinal cord. There are no effective cures, albeit three drugs, riluzole, edaravone, and AMX0035 (a combination of sodium phenylbutyrate and taurursodiol), have been approved by the Food and Drug Administration, with limited improvement in patients. There is an urgent need to build better and more effective treatment strategies for ALS. Since the disease is very heterogenous, numerous approaches have been explored, such as targeting genetic mutations, decreasing oxidative stress and excitotoxicity, enhancing mitochondrial function and protein degradation mechanisms, and inhibiting neuroinflammation. In addition, various chemical libraries or previously identified drugs have been screened for potential repurposing in the treatment of ALS. Here, we review previous drug discovery efforts targeting a variety of cellular pathologies that occur from genetic mutations that cause ALS, such as mutations in SOD1, C9orf72, FUS, and TARDP‐43 genes. These mutations result in protein aggregation, which causes neuronal degeneration. Compounds used to target cellular pathologies that stem from these mutations are discussed and comparisons among different preclinical models are presented. Because the drug discovery landscape for ALS and other motor neuron diseases is changing rapidly, we also offer recommendations for a novel, more effective, direction in ALS drug discovery that could accelerate translation of effective compounds from animals to patients.

An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013–2023)

“…These new hepatitis C drugs are further notable for their complexity, stereochemical richness, use of symmetry, diversity of substituents, and use of the uncommon quinoxaline nitrogen heterocycle along with a pyrrolidine and in many cases a nitrogen-containing macrocycle . This dataset also includes five new migraine and six new diabetes small-molecule drugs as well as new Parkinson’s disease, MS, and ALS medications. Multiple new small-molecule treatments for eye-, skin-, and bowel-related conditions have emerged during the past decade.…”