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.

Keywords: amyotrophic lateral sclerosis; cellular pathologies; gene mutations; inhibition; protein aggregation.

FIGURE 1

Statistical representation of the genes contributing to sALS. ALS, amyotrophic lateral sclerosis; sALS, sporadic ALS. [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Statistical representation of the genes contributing to fALS. ALS, amyotrophic lateral sclerosis; fALS, familial ALS. [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

The formation and degradation of misfolded proteins inside the neuron cells. [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 4

The 1.25 Å resolution X-ray crystal structure of the SOD1^A4V mutant dimer covalently linked with two molecules of 47, shown as salmon and cyan, via a selenium-sulfur linkage on each monomer’s Cys111 residue. The selenium and sulfur atoms are shown in ball and stick style and colored magenta and yellow, respectively, while chains A and B are represented in ribbon form and colored teal and orange, respectively. [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 5

Elaboration of isoproterenol to 54.

FIGURE 6

Optimization of the aromatic moiety in ASP. ASP, arylsulfanylpyrazolone.

FIGURE 7

Pharmacokinetic properties of 65.

FIGURE 8

Pharmacokinetic properties of 66.

FIGURE 9

Pharmacokinetic properties of 68.

FIGURE 10

Pharmacokinetic properties of 73.

FIGURE 11

Pharmacokinetic properties of 78.

FIGURE 12

Pharmacokinetic properties of PYT 83.

FIGURE 13

Analogues of 83 for improved metabolic stability and solubility.

SCHEME 1

Synthesis of 1,3,4-oxadiazoles (9).

SCHEME 2

Covalent binding of compound 19.

SCHEME 3

Synthesis of compounds 19 and 41–48.

SCHEME 4

Synthesis of tertiary amine pyrazolone 66 and its most potent salt (68).

SCHEME 5

Synthesis of (+)-78.

SCHEME 6

Synthesis of fluorinated PYT inhibitors.

SCHEME 7

Synthesis of chemical chaperon 90.

SCHEME 8

Synthesis of benzimidazole derivatives.

SCHEME 9

Synthesis of 6-trifluoromethylbenzo[d]thiazol2-arylacetamide analogues.