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| Formula | C16H20Cl2N2O |
| Molar mass | 327.25 g·mol−1 |
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Brasofensine (NS-2214, BMS-204756) is aphenyltropane dopamine reuptake inhibitor that had been underdevelopment byBristol-Myers Squibb and defunct companyNeuroSearch for the treatment ofParkinson's andAlzheimer's diseases.
In 1996, brasofensine entered phase I trials in the United States and phase II trials in Denmark.[1] From 1996 to 1999,Bristol-Myers Squibb (BMS) was involved in development and testing before exiting the collaboration with NeuroSearch. In 2001, its development was confirmed to be discontinued.[2]
Inanimal models of Parkinson's disease, brasofensine was effective instimulating locomotor activity and reversingakinesia.[3]Phase II trials in humans were conducted in 1996 and brasofensine was shown to be both effective and well tolerated at a dose of 4 mg;[4] however, development was stopped afterin vivo cis-anti isomerization of the 2α-methyloxime group was reported.[5]
In Parkison's disease, symptoms do not begin to manifest until there has been an 80% reduction in dopaminergic neurons, particularly in thesubstantia nigra brain region.
Brasofensine is not particularly stable and is readily metabolized. It was studied in humans in doses ranging from 2-50 mg.[6] Because metabolism in rats is much greater than in humans, the amount of metabolites detected in their urine (andfeces) was also much greater than for humans, who excrete more of the product intact. Inradiolabeling studies using14C, most (~90%) of the14C was detected in theurine of humans, whereas for rats as much as 80% of the14C was in their feces.[6]
Theisomerization of brasofensine did not involveepimerization at 2-position of the tropane ring, but rather involved theE/Z-isomerization of theimine (i.e. "methyl-aldoxime").[6] It was believed that this process occursin vivo, although it cannot be ruled out as a possibility that some isomerization also occurs prior to ingestion. The (Z)-isomer has been assigned the name BMS-205912.
Imine formation is a reversible process, and in the study by Zhuet al.,[6] none of the aldehyde was recovered/detected byGC-MS. Instead, the breakdown products wereN-demethylated metabolites.
