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

Ondrej Stepanek; Niyada Hin; Ajit G Thomas; Ranjeet P Dash; Jesse Alt; Rana Rais; Camilo Rojas; Barbara S Slusher; Takashi Tsukamoto

doi:10.1016/j.ejmech.2019.03.015

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

Eur J Med Chem. 2019 May 15:170:276-289. doi: 10.1016/j.ejmech.2019.03.015. Epub 2019 Mar 9.

Authors

Ondrej Stepanek¹, Niyada Hin¹, Ajit G Thomas¹, Ranjeet P Dash², Jesse Alt¹, Rana Rais², Camilo Rojas³, Barbara S Slusher², Takashi Tsukamoto⁴

Affiliations

¹ Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD, 21205, USA.
² Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD, 21205, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD, 21205, USA.
³ Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD, 21205, USA; Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD, 21205, USA.
⁴ Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD, 21205, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD, 21205, USA. Electronic address: ttsukamoto@jhmi.edu.

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.

Keywords: Ceramide; Glucuronidation; Neutral sphingomyelinase 2; Phosphodiesterase; Sphingomyelin.

MeSH terms

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

Substances

Enzyme Inhibitors
Imidazoles
Phenols
imidazole
SMPD3 protein, human
Sphingomyelin Phosphodiesterase

Abstract

MeSH terms

Substances

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