title: Deuteration and fluorination of 1,3-bis(2-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione to improve its pharmacokinetic properties.
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.
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, USA.
authors.forename: Guoyao
authors.initials: G
authors.lastname: Xia
authors.affiliation: Cambria Pharmaceuticals, Cambridge, MA 02142, USA.
authors.forename: Radhia
authors.initials: R
authors.lastname: Benmohamed
authors.affiliation: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208-3500, USA.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
authors.affiliation: Cambria Pharmaceuticals, Cambridge, MA 02142, USA.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Kirsch
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, USA; Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA. Electronic address: Agman@chem.northwestern.edu.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D003903:Deuterium / Q000737:chemistry; D006207:Half-Life; D054879:Halogenation; D006801:Humans; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D011744:Pyrimidinones / Q000737:chemistry* / Q000493:pharmacokinetics; D012995:Solubility
chemical_list: D011744:Pyrimidinones; D003903:Deuterium
keywords: ADME; Amyotrophic lateral sclerosis (ALS); Deuteration; Fluorination; Microsome stability; Pharmacokinetics; Pyrimidine-2,4,6-triones (PYT)