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

Guoyao Xia, Radhia Benmohamed, Richard I. Morimoto, Donald R. Kirsch, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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. Over 200 pyrimidine-2,4,6-trione (PYT) small molecules, which prevent aggregation and reduce the associated toxicity of mutant superoxide dismutase 1 (SOD1) found in patients with familial ALS, have been synthesized and tested. One of the compounds (1,3-bis(2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione, (1) was previously found to have an excellent combination of potency efficacy, and some desirable pharmacokinetic properties. To improve the solubility and metabolic stability properties of this compound, deuterium and fluorine were introduced into 1. New analogs with better solubility, plasma stability, and human microsome stability were identified.

Original languageEnglish (US)
Pages (from-to)5098-5101
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number21
DOIs
StatePublished - Nov 1 2014

Keywords

  • ADME
  • Amyotrophic lateral sclerosis (ALS)
  • Deuteration
  • Fluorination
  • Microsome stability
  • Pharmacokinetics
  • Pyrimidine-2,4,6-triones (PYT)

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine
  • Molecular Biology
  • Biochemistry
  • Clinical Biochemistry
  • Pharmaceutical Science
  • Organic Chemistry

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