5-Aminocoumarans:  Dual Inhibitors of Lipid Peroxidation and Dopamine Release with Protective Effects against Central Nervous System Trauma and Ischemia

Abstract

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.

Raxofelast (IRFI 016): A New Hydrophilic Vitamin E‐Like Antioxidant Agent

“…An analysis of rat urine samples treated with P-glucuronidase showed partial conjugation of IRFI 045 with glucuronic acid, although it was significant only at the highest doses of the parent compound. The absence of a detectable conjugation for IRFI 005 is noteworthy feature of the compound, since the metabolic inactivation due to the ease of formation of 0-glucuronide and 0-sulfate on the phenolic hydroxy group was viewed as one of the major disadvantages of tocopherol-like phenolic antioxidants (29).…”

(1R,2R)-8-Bromo-1-[(E)-2-(4-bromophenyl)ethenyl]-2-nitro-1,2-dihydronaphtho[2,1-b]furan

“…The title compound has a dihydrobenzofuran skeleton, which is the effective physiologically active component in many medicinal plants (Ohkawa et al 1997;Snyder et al, 2011). The molecular structure of the title compound is shown in Fig.…”

A General Approach to Indoles: Practical Applications for the Synthesis of Highly Functionalized Pharmacophores

“…In addition, 2,3-dihydrobenzofurans have been developed for treatment of traumatic and ischemic CNS injury [58], and are reported to be useful in the treatment of arteriosclerosis, hepatopathy, and cerebrovasculary disease [59]. While there are a multitude of methods for the preparation of 2,3-dihydrobenzofurans, strategies which provide rapid access to the 2,3-dihydrobenzofuran ring system not accessible through current synthetic techniques are invaluable.…”