Novel 21-Aminosteroids that Inhibit Iron-Dependent Lipid Peroxidation and Protect against Central Nervous System Trauma

E. Jon Jacobsen; John M. McCall; Donald E. Ayer; Fred J. VanDoornik; John R. Palmer; Kenneth L. Belonga; J. Mark Braughler; Edward D. Hall; David J. Houser; Mark A. Krook; Thomas A. Runge

doi:10.1021/jm00166a010

Novel 21-Aminosteroids that Inhibit Iron-Dependent Lipid Peroxidation and Protect against Central Nervous System Trauma

E. Jon Jacobsen, John M. McCall, Donald E. Ayer, Fred J. VanDoornik, John R. Palmer, Kenneth L. Belonga, J. Mark Braughler, Edward D. Hall, David J. Houser, Mark A. Krook, Thomas A. Runge

Neuroscience

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

107 Scopus citations

Abstract

A novel class of 21-aminosteroids has been developed. Compounds within this series are potent inhibitors of iron-dependent lipid peroxidation in rat brain homogenates with IC₅₀'s as low as 3 μM. Furthermore, selected members enhance early neurological recovery and survival in a mouse head injury model. Significant improvement in the 1 h post-head-injury neurological status (grip test score) by as much as 168.6% of the control has been observed. The most efficacious compound in this assay (30) showed an increase in the 1-week survival of 78.6% as compared to 27.3% for the vehicle-treated mice in the head-injury model. Based on its biological profile, 21-[4-(2,6-di-1- pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16α-methylpregna-1,4,9(11)-triene-3,20-dione monomethanesulfonate (30) was selected for further evaluation and is currently entering phase I clinical trials for the treatment of head and spinal trauma.

Original language	English
Pages (from-to)	1145-1151
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	33
Issue number	4
DOIs	https://doi.org/10.1021/jm00166a010
State	Published - Apr 1990

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Jon Jacobsen, E., McCall, J. M., Ayer, D. E., VanDoornik, F. J., Palmer, J. R., Belonga, K. L., Braughler, J. M., Hall, E. D., Houser, D. J., Krook, M. A., & Runge, T. A. (1990). Novel 21-Aminosteroids that Inhibit Iron-Dependent Lipid Peroxidation and Protect against Central Nervous System Trauma. Journal of Medicinal Chemistry, 33(4), 1145-1151. https://doi.org/10.1021/jm00166a010

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title = "Novel 21-Aminosteroids that Inhibit Iron-Dependent Lipid Peroxidation and Protect against Central Nervous System Trauma",

abstract = "A novel class of 21-aminosteroids has been developed. Compounds within this series are potent inhibitors of iron-dependent lipid peroxidation in rat brain homogenates with IC50's as low as 3 μM. Furthermore, selected members enhance early neurological recovery and survival in a mouse head injury model. Significant improvement in the 1 h post-head-injury neurological status (grip test score) by as much as 168.6% of the control has been observed. The most efficacious compound in this assay (30) showed an increase in the 1-week survival of 78.6% as compared to 27.3% for the vehicle-treated mice in the head-injury model. Based on its biological profile, 21-[4-(2,6-di-1- pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16α-methylpregna-1,4,9(11)-triene-3,20-dione monomethanesulfonate (30) was selected for further evaluation and is currently entering phase I clinical trials for the treatment of head and spinal trauma.",

author = "{Jon Jacobsen}, E. and McCall, {John M.} and Ayer, {Donald E.} and VanDoornik, {Fred J.} and Palmer, {John R.} and Belonga, {Kenneth L.} and Braughler, {J. Mark} and Hall, {Edward D.} and Houser, {David J.} and Krook, {Mark A.} and Runge, {Thomas A.}",

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AU - Ayer, Donald E.

AU - VanDoornik, Fred J.

AU - Palmer, John R.

AU - Belonga, Kenneth L.

AU - Braughler, J. Mark

AU - Hall, Edward D.

AU - Houser, David J.

AU - Krook, Mark A.

AU - Runge, Thomas A.

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N2 - A novel class of 21-aminosteroids has been developed. Compounds within this series are potent inhibitors of iron-dependent lipid peroxidation in rat brain homogenates with IC50's as low as 3 μM. Furthermore, selected members enhance early neurological recovery and survival in a mouse head injury model. Significant improvement in the 1 h post-head-injury neurological status (grip test score) by as much as 168.6% of the control has been observed. The most efficacious compound in this assay (30) showed an increase in the 1-week survival of 78.6% as compared to 27.3% for the vehicle-treated mice in the head-injury model. Based on its biological profile, 21-[4-(2,6-di-1- pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16α-methylpregna-1,4,9(11)-triene-3,20-dione monomethanesulfonate (30) was selected for further evaluation and is currently entering phase I clinical trials for the treatment of head and spinal trauma.

AB - A novel class of 21-aminosteroids has been developed. Compounds within this series are potent inhibitors of iron-dependent lipid peroxidation in rat brain homogenates with IC50's as low as 3 μM. Furthermore, selected members enhance early neurological recovery and survival in a mouse head injury model. Significant improvement in the 1 h post-head-injury neurological status (grip test score) by as much as 168.6% of the control has been observed. The most efficacious compound in this assay (30) showed an increase in the 1-week survival of 78.6% as compared to 27.3% for the vehicle-treated mice in the head-injury model. Based on its biological profile, 21-[4-(2,6-di-1- pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16α-methylpregna-1,4,9(11)-triene-3,20-dione monomethanesulfonate (30) was selected for further evaluation and is currently entering phase I clinical trials for the treatment of head and spinal trauma.

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Novel 21-Aminosteroids that Inhibit Iron-Dependent Lipid Peroxidation and Protect against Central Nervous System Trauma

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