Quantitative analysis of the kinetic constant of the reaction of N,N'-propylenedinicotinamide with the hydroxyl radical using dimethyl sulfoxide and deduction of its structure in chloroform.
N,N'-Propylenedinicotinamide (Nicaraven) is presently being developed for the treatment of cerebral stroke including subarachnoid hemorrhage. This drug is promising because some data suggest it to have an ability to scavenge the hydroxyl radical under physiological conditions in vivo, while it also has a high permeability through the blood brain barrier. Using the kinetic constant of the reaction between the hydroxyl radical and dimethyl sulfoxide, the formula derived by Babbs and Griffin (Free Rad. Biol. Med., 6 1989) was applied to obtain the kinetic constant of Nicaraven with the hydroxyl radical using a dimethyl sulfoxide-xanthine oxidase-hypoxanthine-Fe system, and this yielded the kinetic constant 3.4x10(9) M(-1) s(-1) (1 M=1 mol dm(-3)) for Nicaraven. Structurally related compounds were also investigated. The amide group of Nicaraven was thus found to play an important part in the reaction with the hydroxyl radical. Methanesulfinic acid, which was obtained from the reaction between dimethyl sulfoxide and the hydroxyl radical, was found to be stable under this adopted experimental condition and therefore was used to quantify the kinetic constant of Nicaraven. The structure of Nicaraven has also been investigated in CDCl3 using IR spectra, computer calculations and 1H-NMR analysis, and Nicaraven was thus shown to have an intramolecular hydrogen bond which forms a 7-membered ring that resembles a part of the 1H-1,4-benzodiazepines. This structure may play an important role in the penetration through the blood brain barrier.
Akimoto
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Fuji Gotemba Research Labs., Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
D000975:Antioxidants / Q000378:metabolism*; D002725:Chloroform; D004121:Dimethyl Sulfoxide / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000378:metabolism*; D006838:Hydrocarbons; D017665:Hydroxyl Radical / Q000378:metabolism*; D007700:Kinetics; D008697:Methane / Q000031:analogs & derivatives; D008956:Models, Chemical; D008958:Models, Molecular; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism
D000975:Antioxidants; D016166:Free Radical Scavengers; D006838:Hydrocarbons; C030011:carbene; D009536:Niacinamide; D017665:Hydroxyl Radical; D002725:Chloroform; D008697:Methane; C042625:nicaraven; D004121:Dimethyl Sulfoxide