Neutral sphingomyelinase 2 inhibitors based on the 4-(1H-imidazol-2-yl)-2,6-dialkoxyphenol scaffold.

Abstract

Neutral sphingomyelinase 2 (nSMase2), a key enzyme in ceramide biosynthesis, is a new therapeutic target for the treatment of neurological disorders and cancer. Using 2,6-dimethoxy-4-[4-phenyl-5-(2-thienyl)-1H-imidazol-2-yl]phenol (DPTIP), our initial hit compound (IC50 = 30 nM) from nSMase2 screening efforts, as a molecular template, a series of 4-(1H-imidazol-2-yl)-2,6-dialkoxyphenol derivatives were designed, synthesized, and evaluated. Systematic examination of various regions of DPTIP identified the key pharmacophore required for potent nSMase2 inhibition as well as a number of compounds with the 4-(1H-imidazol-2-yl)-2,6-dialkoxyphenol scaffold with similar or higher inhibitory potency against nSMase2 as compared to DPTIP. Among them, 4-(4,5-diisopropyl-1H-imidazol-2-yl)-2,6-dimethoxyphenol (25b) was found to be metabolically stable against P450 metabolism in liver microsomes and displayed higher plasma exposure following oral administration as compared to DPTIP. Analysis of plasma samples identified an O-glucuronide as the major metabolite. Blockade of the phase II metabolism should further facilitate our efforts to identify potent nSMase2 inhibitors with desirable ADME properties.

• Authors: Ondrej Stepanek, Niyada Hin, Ajit G Thomas, Ranjeet P Dash, Jesse Alt, Rana Rais, Camilo Rojas, Barbara S Slusher, Takashi Tsukamoto
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 170 Pg. 276-289 (May 15 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 30921693 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Imidazoles
• Phenols
• imidazole
• SMPD3 protein, human
• Sphingomyelin Phosphodiesterase

Topics

• Animals
• Enzyme Inhibitors (chemistry, metabolism, pharmacokinetics, pharmacology)
• Humans
• Imidazoles (chemistry, metabolism, pharmacokinetics, pharmacology)
• Male
• Mice
• Microsomes, Liver (metabolism)
• Phenols (chemistry, metabolism, pharmacokinetics, pharmacology)
• Sphingomyelin Phosphodiesterase (antagonists & inhibitors, metabolism)