5-aminocoumarans: dual inhibitors of lipid peroxidation and dopamine release with protective effects against central nervous system trauma and ischemia.
A series of 2,3-dihydro-5-benzofuranamines (5-aminocoumarans) were developed for the treatment of traumatic and ischemic central nervous system (CNS) injury. Compounds within this class were extremely effective inhibitors of lipid peroxidation in vitro and antagonized excitatory behavior coupled with peroxidative injury induced by spinal intrathecal injection of FeCl2 (mouse-FeCl2-it assay) in vivo. Selected compounds were tested for antagonistic activity on methamphetamine (MAP)-induced hypermotility resulting from dopamine release in the mouse brain. Among the compounds synthesized, compound 26n (2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl) methyl]-5-benzofuranamine) exhibited potent effects in these assays (inhibition of lipid peroxidation, IC50 = 0.07 microM; mouse-FeCl2-it assay, ID50 = 10.4 mg/ kg, po; MAP-induced hypermotility, 98% inhibition, 10 mg/kg, ip). The S-(+)-form of compound 26n dihydrochloride (TAK-218), which has 30 times more potent antagonistic activity on MAP-induced hypermotility than the R-(-)-form, improved more significantly the survival rate in the cerebral ischemia model (rat, 1-3 mg/kg, ip) during the period of 1-14 days after ischemia and decreased functional disorders in the traumatic brain injury model (rat, 0.1-1 mg/kg, ip) 3-14 days after injury. These results imply a role for dopamine in deterioration of CNS function after ischemic and traumatic injury. TAK-218 is a promising compound for the treatment of stroke and CNS trauma and is now under clinical investigation.
Ohkawa
S
S
Pharmaceutical Research Laboratories I, Takeda Chemical Industries, Ltd., Osaka, Japan.
Fukatsu
K
K
Miki
S
S
Hashimoto
T
T
Sakamoto
J
J
Doi
T
T
Nagai
Y
Y
Aono
T
T
D000818:Animals; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy; D002490:Central Nervous System / Q000098:blood supply / Q000293:injuries*; D004298:Dopamine / Q000378:metabolism*; D005296:Ferrous Compounds / Q000494:pharmacology; D007536:Isomerism; D008054:Lipid Peroxides / Q000378:metabolism*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D001572:Benzofurans; D005296:Ferrous Compounds; D008054:Lipid Peroxides; C104755:TAK 218; C043168:coumaran; C029451:ferrous chloride; D004298:Dopamine