Synthesis and Biological Evaluation of the 1-Arylpyrazole Class of σ1 Receptor Antagonists: Identification of 4-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862)
- 27 July 2012
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 55 (19), 8211-8224
- https://doi.org/10.1021/jm3007323
Abstract
The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ(1) receptor (σ(1)R) antagonists are reported. The new compounds were evaluated in vitro in human σ(1)R and guinea pig σ(2) receptor (σ(2)R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be necessary, in accordance with known receptor pharmacophores. A wide variety of amines and spacer lengths between the amino and pyrazole groups were tolerated, but only the ethylenoxy spacer and small cyclic amines provided compounds with sufficient selectivity for σ(1)R vs σ(2)R. The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862), which showed high activity in the mouse capsaicin model of neurogenic pain, emerged as the most interesting candidate. In addition, compound 28 exerted dose-dependent antinociceptive effects in several neuropathic pain models. This, together with its good physicochemical, safety, and ADME properties, led compound 28 to be selected as clinical candidate.Keywords
This publication has 37 references indexed in Scilit:
- Sigma 1 Receptor Chaperone: Pharmacology and Therapeutic PerspectivesPublished by Wiley ,2012
- Novel Potent and Selective σ Ligands: Evaluation of Their Agonist and Antagonist PropertiesJournal of Medicinal Chemistry, 2011
- The sigma-1 receptor chaperone as an inter-organelle signaling modulatorTrends in Pharmacological Sciences, 2010
- σ1 Receptor Modulation of G-Protein-Coupled Receptor Signaling: Potentiation of Opioid Transduction Independent from Receptor BindingPublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2010
- The pharmacology of sigma-1 receptorsPharmacology & Therapeutics, 2009
- Neurosteroid dehydroepiandrosterone sulphate inhibits persistent sodium currents in rat medial prefrontal cortex via activation of sigma-1 receptorsExperimental Neurology, 2008
- Cloning and Functional Expression of the Human Type 1 Sigma Receptor (hSigmaR1)Biochemical and Biophysical Research Communications, 1996
- Purification, molecular cloning, and expression of the mammalian sigma1-binding site.Proceedings of the National Academy of Sciences of the United States of America, 1996
- A proposal for the classification of sigma binding sitesTrends in Pharmacological Sciences, 1992
- N-methyl-D-aspartate-induced neuronal activation is selectively modulated by σ receptorsEuropean Journal of Pharmacology, 1990