@article{b35b829598844249a6d4b2356225912b,
title = "Discovery of a novel class of potent and selective tetrahydroindazole-based sigma-1 receptor ligands",
abstract = "The sigma-1 and sigma-2 receptors have been shown to play important roles in CNS diseases, cancer, and other disorders. These findings suggest that targeting these proteins with small-molecule modulators may be of important therapeutic value. Here we report the development of a new class of tetrahydroindazoles that are highly potent and selective ligands for sigma-1. Molecular modeling was used to rationalize the observed structure-activity relationships and identify key interactions responsible for increased potency of the optimized compounds. Assays for solubility and microsomal stability showed this series possesses favorable characteristics and is amenable to further therapeutic development. The compounds described herein will be useful in the development of new chemical probes for sigma-1 and to aid in future work therapeutically targeting this protein.",
author = "Iyamu, {Iredia D.} and Wei Lv and Neha Malik and Mishra, {Rama K.} and Schiltz, {Gary E.}",
note = "Funding Information: Financial support has been provided by the National Cancer Institute of the National Institutes of Health under Award Number CA189074 (GES). 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 National Cancer Institute awarded to the Robert H. Lurie Comprehensive Cancer Center . We thank Dr. Atul Jain for assistance in editing the manuscript. Ki determinations were generously provided by the National Institute of Mental Health 's Psychoactive Drug Screening Program, Contract # HHSN-271-2018-00023-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. For experimental details about the sigma binding assays, please see the PDSP website http://pdsp.med.unc.edu/. Funding Information: Financial support has been provided by the National Cancer Institute of the National Institutes of Health under Award Number CA189074 (GES). 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 National Cancer Institute awarded to the Robert H. Lurie Comprehensive Cancer Center. We thank Dr. Atul Jain for assistance in editing the manuscript. Ki determinations were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # HHSN-271-2018-00023-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. For experimental details about the sigma binding assays, please see the PDSP website http://pdsp.med.unc.edu/. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",
year = "2019",
month = may,
day = "1",
doi = "10.1016/j.bmc.2019.03.030",
language = "English (US)",
volume = "27",
pages = "1824--1835",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "9",
}
