Synthesis and biological evaluation of Esaprazole analogues showing σ1 binding and neuroprotective properties in vitro.

Abstract

Esaprazole, a molecule previously acknowledged to protect against stomach and intestinal ulcers was surprisingly discovered to have neuroprotective activities and σ1 binding in vitro. A highly diverse set of Esaprazole analogues 2-5 was prepared in order to increase blood-brain barrier penetration. The analogues showed a structure-activity relationship at the σ1 receptor closely matching already published pharmacophores. Many of the analogues were shown to have neuroprotective properties in two assays using primary cultures of cortical neurons exposed to glutamate and hydrogen peroxide. However, no apparent SAR for these two assays could be developed. Metabolic stability of the analogues were also investigated and the structure of R(1) had a significant bearing on the ADME properties of the compound resulting in two series of compounds. Compounds in which R(1) was a H or acyl group had good metabolic stability in RLM but poor BBB penetration, whereas compounds where R(1) was a cyclo- or bicyclo-alkyl group had poor metabolic stability but good BBB penetration.

• Authors: Nicholas M Kelly, Anja Wellejus, Heidi Elbrønd-Bek, Morten Sloth Weidner, Signe Humle Jørgensen
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 21 Issue 11 Pg. 3334-47 (Jun 01 2013) ISSN: 1464-3391 [Electronic] England
• PMID: 23601816 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Ulcer Agents
• Neuroprotective Agents
• Piperazines
• Receptors, sigma
• esaprazole
• Glutamic Acid
• Hydrogen Peroxide

Topics

• Animals
• Anti-Ulcer Agents (chemical synthesis, chemistry, pharmacology)
• Blood-Brain Barrier (metabolism)
• Capillary Permeability
• Cerebral Cortex (cytology, drug effects, metabolism)
• Drug Stability
• Glutamic Acid (pharmacology)
• Hydrogen Peroxide (pharmacology)
• Neurons (cytology, drug effects, metabolism)
• Neuroprotective Agents (chemical synthesis, chemistry, pharmacology)
• Piperazines (chemical synthesis, chemistry, pharmacology)
• Primary Cell Culture
• Protein Binding
• Radioligand Assay
• Rats
• Receptors, sigma (agonists, metabolism)
• Structure-Activity Relationship