Novel 21-aminosteroids that inhibit iron-dependent lipid peroxidation and protect against central nervous system trauma.
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 microM. 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]-16 alpha- 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.
Jacobsen
E J
EJ
CNS Research, Upjohn Company, Kalamazoo, Michigan 49001.
McCall
J M
JM
Ayer
D E
DE
Van Doornik
F J
FJ
Palmer
J R
JR
Belonga
K L
KL
Braughler
J M
JM
Hall
E D
ED
Houser
D J
DJ
Krook
M A
MA
D000588:Amines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis*; D006259:Craniocerebral Trauma / Q000188:drug therapy / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D051379:Mice; D011281:Pregnatrienes / Q000494:pharmacology*; D051381:Rats; D013124:Spinal Injuries / Q000188:drug therapy; D013256:Steroids / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000588:Amines; D000975:Antioxidants; D011281:Pregnatrienes; D013256:Steroids; C053355:tirilazad