Discovery of a novel class of potent and selective tetrahydroindazole-based sigma-1 receptor ligands

Iredia D. Iyamu; Wei Lv; Neha Malik; Rama K. Mishra; Gary E. Schiltz

doi:10.1016/j.bmc.2019.03.030

Discovery of a novel class of potent and selective tetrahydroindazole-based sigma-1 receptor ligands

Iredia D. Iyamu, Wei Lv, Neha Malik, Rama K. Mishra, Gary E. Schiltz^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1824-1835
Number of pages	12
Journal	Bioorganic and Medicinal Chemistry
Volume	27
Issue number	9
DOIs	https://doi.org/10.1016/j.bmc.2019.03.030
State	Published - May 1 2019

Funding

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/. 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/.

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2019.03.030

Cite this

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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.",

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Discovery of a novel class of potent and selective tetrahydroindazole-based sigma-1 receptor ligands

Abstract

Funding

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UN SDGs

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