2-(Aminomethyl)chromans that inhibit iron-dependent lipid peroxidation and protect against central nervous system trauma and ischemia

• Published in: Journal of medicinal chemistry 1992-11, Vol.35 (23), p.4464-4472
• Main Authors: Jacobsen, E. Jon, VanDoornik, Fred J, Ayer, Donald E, Belonga, Kenneth L, Braughler, J. Mark, Hall, Edward D, Houser, David J
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - therapeutic use; Brain Ischemia - drug therapy; Central Nervous System - drug effects; Chemistry; Chromans - chemical synthesis; Chromans - chemistry; Chromans - therapeutic use; Exact sciences and technology; Gerbillinae; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Lipid Peroxidation - drug effects; Male; Mice; Organic chemistry; Preparations and properties; Rats; Structure-Activity Relationship; Wounds and Injuries - prevention & control
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00101a025

A series of 2-(aminomethyl)chromans was developed as potent inhibitors of iron-dependent lipid peroxidation. Compounds within this class are extremely effective at inhibiting lipid peroxidation with IC50's as low as 0.2 microM. Selected members were found to enhance early neurological recovery and survival in a mouse head injury model. In this assay, improvement in the 1-h post-head-injury neurological status (grip test score) by as much as 230% of control was observed. One of the most efficacious compounds (35) was evaluated in two models of cerebral ischemia where significant neuroprotection was observed. These results provide further support for the importance of cerebroprotective antioxidants for the treatment of traumatic and ischemic injury as well as additional evidence for the role of oxygen radicals in postischemic brain damage.