Pyrimidine-2,4,6-trione Derivatives and Their Inhibition of Mutant SOD1-Dependent Protein Aggregation. Toward a Treatment for Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness, paralysis, and death, most often from respiratory failure. The only FDA approved drug for the treatment of ALS, riluzole, only extends the median survival in patients by 2–3 months. There is an urgent need for novel therapeutic strategies for this devastating disease. Using a high-throughput screening assay targeting an ALS cultured cell model (PC12-G93A-YFP cell line), we previously identified three chemotypes that were neuroprotective. We present a further detailed analysis of one promising scaffold from that group, pyrimidine-2,4,6-triones (PYTs), characterizing a number of PYT analogs using SAR and ADME. The PYT compounds show good potency, superior ADME data, low toxicity, brain penetration, and excellent oral bioavailability. Compounds from this series show 100% efficacy in the protection assay with a good correlation in activity between the protection and protein aggregation assays. The modifications of the PYT scaffold presented here suggest that this chemical structure may be a novel drug candidate scaffold for use in clinical trials in ALS.

CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease

“…1.3 to that with Ca V 1.2). The scaffold also was of interest because of its favourable pharmacological and absorption, distribution, metabolism and excretion (ADME) properties, as well as low toxicity, brain penetration and oral bioavailability, as previously determined 21 .…”

Deuteration and fluorination of 1,3-bis(2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione to improve its pharmacokinetic properties

“…The fluorine atoms were introduced into the carbon chains of 1 with DAST followed by standard urea synthesis and PYT ring closing 7 . The fluorine atoms decreased the potency of the PYT analogues in comparison to 1 and 5 .…”

“…The pharmacokinetic properties of the fluorinated PYT compounds were much improved (compare 1 and 5 ). m -Fluorine substitution on the Ph ring of the parent compound lowered the potency and stability slightly (compare 1 and 9 7 or 5 and 8 ). Interestingly, fluorine substitution on the phenyl ring lowered solubility (compare 1 and 9 ), but fluorine substitution on the side chain enhanced solubility (compare 1 and 5 ); when fluorine was added to the phenyl rings of 5 to give 8 , the solubility decreased relative to that of 5 .…”

“…7 More than 200 PYT compounds were synthesized, and some general observations about the SAR were concluded. As shown in Figure 1, compound 1 from our previous work was identified as one of the best analogues, having good potency, low toxicity (maximum tolerated dose is 100 mg/kg), and good oral and brain absorption; however, the solubility, microsome stability, and plasma stability of this compound was not very satisfactory (see also Supporting Information SP-1 for details), and further improvement was needed.…”

Molecular Structure, Spectroscopic and DFT Computational Studies of Arylidene-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione

“…Several examples of the arylidene derivatives of barbituric acid possessing significant implementation in the pharmaceutical field such as antitumor [1], immunomodulating, matrix metalloproteinase (MMP) inhibitor [2], antioxidant [3], antibacterial agent [4], anticonvulsant potentials [5], and mutant SOD1-dependent protein aggregation [6] were investigated. Additionally, these compounds were shown to haveseveral targets in dye manufacturing [7], supramolecular chemistry [8], and in nonlinear optical study [9].…”