NOVEL 21-AMINOSTEROIDS THAT INHIBIT IRON-DEPENDENT LIPID-PEROXIDATION AND PROTECT AGAINST CENTRAL-NERVOUS-SYSTEM TRAUMA

被引:100
作者
JACOBSEN, EJ [1 ]
MCCALL, JM [1 ]
AYER, DE [1 ]
VANDOORNIK, FJ [1 ]
PALMER, JR [1 ]
BELONGA, KL [1 ]
BRAUGHLER, JM [1 ]
HALL, ED [1 ]
HOUSER, DJ [1 ]
KROOK, MA [1 ]
RUNGE, TA [1 ]
机构
[1] UPJOHN CO,CHEM RES PREPARAT,KALAMAZOO,MI 49001
关键词
D O I
10.1021/jm00166a010
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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. © 1990, American Chemical Society. All rights reserved.
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页码:1145 / 1151
页数:7
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