The sigma 1 receptor is a multifunctional receptor with wide distribution in the nervous system and its function has been implicated with a number of neurological disorders including dementia and Alzheimer's disease (AD) and other neurodegenerative disorders. In addition, modulators of σ1 have been advanced into clinical trials for the treatment of pain. Starting from our previously disclosed piperidine scaffold, we have identified a class of potent sigma 1 modulators. This work highlights the key SAR components that lead to the divergence in D and σ1 activity. In addition, we further profile lead compounds in a panel of off-target receptors, in vitro and in vivo pharmacokinetic studies. This has culminated in the discovery of multiple σ1 receptor modulators with properties that will allow for study in animal models.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.ejmech.2022.114840 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Reactivity of Anomalous Aziridines for Versatile Access to High Fsp Amine Chemical Space.
Acc Chem Res
January 2025
Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, Wisconsin 53706, United States.
ConspectusThe manipulation of strained rings is a powerful strategy for accessing the valuable chemical frameworks present in natural products and active pharmaceutical ingredients. Aziridines, the smallest N-containing heterocycles, have long served as building blocks for constructing more complex amine-containing scaffolds. Traditionally, the reactivity of typical aziridines has been focused on ring-opening by nucleophiles or the formation of 1,3-dipoles.
View Article and Find Full Text PDFPhenotype-Led Identification of IL-10 Upregulators in Human CD4 T-cells and Elucidation of Their Pharmacology as Highly Selective CDK8/CDK19 Inhibitors.
J Med Chem
January 2025
Immunology Research Unit GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
Therapeutics promoting the endogenous production of IL-10 have the potential to restore homeostasis in inflammatory disorders such as inflammatory bowel disease (IBD). Here we describe the identification of a series of IL-10 upregulators based on a pyrimidyl-piperidine scaffold through a high throughput phenotypic CD4 T-cell multiplex assay. optimization of the initial hit yielded a lead with good potency and an clearance profile, compound 3-7, which additionally demonstrated efficacy in a murine endotoxin challenge PK-PD mechanistic model.
View Article and Find Full Text PDFSelective Synthesis of Tetrahydroisoquinoline and Piperidine Scaffolds by Oxidative Ring Opening/Ring Closing Protocols of Substituted Indenes and Cyclopentenes.
ChemistryOpen
December 2024
MTA TTK Lendület Artificial Transporter Research Group, Institute of Materials and Environmental Chemistry, HUN-REN Research Center for Natural Sciences, H-1117, Budapest, Magyar tudósok krt. 2, Hungary.
Novel tetrahydroisoquinoline and piperidine derivatives were selectively synthesized from substituted indenes or cyclopentenes. The process starts with an oxidative cleavage of the ring olefin bond, which gives reactive diformyl intermediates. By a ring-closing step using chiral (R) or (S) α-methylbenzylamine under a reductive amination protocol facilitated ring formation with ring expansion of the corresponding nitrogen-containing heterocycles.
View Article and Find Full Text PDFUse of a small molecule microarray screen to identify inhibitors of the catalytic RNA subunit of Methanobrevibacter smithii RNase P.
Nucleic Acids Res
January 2025
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA.
Despite interest in developing therapeutics that leverage binding pockets in structured RNAs-whose dysregulation leads to diseases-such drug discovery efforts are limited. Here, we have used a small molecule microarray (SMM) screen to find inhibitors of a large ribozyme: the Methanobrevibacter smithii RNase P RNA (Msm RPR, ∼300 nt). The ribonucleoprotein form of RNase P, which catalyzes the 5'-maturation of precursor tRNAs, is a suitable drug target as it is essential, structurally diverse across life domains, and present in low copy.
View Article and Find Full Text PDFAdvances in the structural modification of Alzheimer's disease drug - Huperzine A.
Bioorg Chem
January 2025
Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. Electronic address:
Article Synopsis
- * Despite its therapeutic benefits, it can cause side effects like dizziness, nausea, and digestive issues, prompting research into ways to improve its effectiveness and safety.
- * This review summarizes 30 years of efforts in modifying Huperzine A's structure and discusses how these changes relate to its activity, aiming to inspire future strategies for better versions of the compound.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!