The development of a new class of inhibitors for betaine-homocysteine S-methyltransferase

• Published in: European journal of medicinal chemistry 2013-07, Vol.65, p.256-275
• Main Authors: Pícha, Jan, Vaněk, Václav, Buděšínský, Miloš, Mládková, Jana, Garrow, Timothy A., Jiráček, Jiří
• Format: Article
• Language: English
• Subjects: Amino acid derivative; Betaine-Homocysteine S-Methyltransferase - antagonists & inhibitors; Betaine-Homocysteine S-Methyltransferase - metabolism; BHMT; Bioisostere; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Homocysteine; Humans; Inhibitor; Molecular Structure; Pentanoic Acids - chemical synthesis; Pentanoic Acids - chemistry; Pentanoic Acids - pharmacology; Phosphinate; Phosphonate; S-Alkylated homocysteine; Structure-Activity Relationship; Sulfides - chemical synthesis; Sulfides - chemistry; Sulfides - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.04.039

Betaine-homocysteine S-methyltransferase (BHMT) is an important zinc-dependent methyltransferase that uses betaine as the methyl donor for the remethylation of homocysteine to form methionine. In the liver, BHMT performs to half of the homocysteine remethylation. In this study, we systematically investigated the tolerance of the enzyme for modifications at the “homocysteine” part of the previously reported potent inhibitor (R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic acid (1). In the new compounds, which are S-alkylated homocysteine derivatives, we replaced the carboxylic group in the “homocysteine” part of inhibitor 1 with different isosteric moieties (tetrazole and oxadiazolone); we suppressed the carboxylic negative charge by amidations; we enhanced acidity by replacing the carboxylate with phosphonic or phosphinic acids; and we introduced pyrrolidine steric constraints. Some of these compounds display high affinity toward human BHMT and may be useful for further pharmacological studies of this enzyme. Although none of the new compounds were more potent inhibitors than the reference inhibitor 1, this study helped to completely define the structural requirements of the active site of BHMT and revealed the remarkable selectivity of the enzyme for homocysteine. [Display omitted] •New inhibitors for betaine-homocysteine S-methyltransferase were synthesized.•Homocysteine binding site of the enzyme was systematically investigated.•Inhibitors were designed using S-alkylated homocysteine as the scaffold.•The results revealed remarkable specificity of the enzyme for homocysteine.