Abstract
The sigma-2 receptor has been shown to play important roles in a number of important diseases, including central nervous system (CNS) disorders and cancer. However, mechanisms by which sigma-2 contributes to these diseases remain unclear. The development of new sigma-2 ligands that can be used to probe the function of this protein and potentially as drug discovery leads is therefore of great importance. Herein we report the development of a series of tetrahydroindazole compounds that are highly potent and selective for sigma-2. Structure–activity relationship data were used to generate a pharmacophore model that summarizes the common features present in the potent ligands. Assays for solubility and microsomal stability showed that several members of this compound series possess promising characteristics for further development of useful chemical probes or drug discovery leads.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1248-1256 |
| Number of pages | 9 |
| Journal | ChemMedChem |
| Volume | 14 |
| Issue number | 13 |
| DOIs | |
| State | Published - Jul 3 2019 |
Funding
Financial support was provided by the National Cancer Institute (NCI) of the US National Institutes of Health under Award Number CA189074 (G.E.S.). Part of this work was performed by the Northwestern University Medicinal and Synthetic Chemistry Core (ChemCore) at the Center for Molecular Innovation and Drug Discovery (CMIDD), which is funded by the Chicago Biomedical Consortium with support from The Searle Funds at The Chicago Community Trust and Cancer Center Support Grant P30 CA060553 from the NCI awarded to the Robert H. Lurie Comprehensive Cancer Center. Sigma-1 and sigma-2 assay data were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract Number HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. For experimental details please refer to the PDSP web site: https://pdspdb.unc.edu/pdspWeb/. Financial support was provided by the National Cancer Institute (NCI) of the US National Institutes of Health under Award Number CA189074 (G.E.S.). Part of this work was performed by the Northwestern University Medicinal and Synthetic Chemistry Core (ChemCore) at the Center for Molecular Innovation and Drug Discovery (CMIDD), which is funded by the Chicago Biomedical Consortium with support from The Searle Funds at The Chicago Community Trust and Cancer Center Support Grant P30 CA060553 from the NCI awarded to the Robert H. Lurie Comprehensive Cancer Center. Sigma-1 and sigma-2 assay data were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract Number HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. For experimental details please refer to the PDSP web site: https://pdspdb.unc.edu/pdspWeb/.
Keywords
- pharmacophores
- sigma-1
- sigma-2
- solubility
- tetrahydroindazoles
ASJC Scopus subject areas
- Drug Discovery
- General Pharmacology, Toxicology and Pharmaceutics
- Molecular Medicine
- Biochemistry
- Pharmacology
- Organic Chemistry
