Brasofensine

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Brasofensine
Clinical data
ATC code
  • none
Legal status
Legal status
Identifiers
  • (+)-(E)-1-[(1R,2R,3S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carbaldehyde O-methyloxime
JSmol)
  • Clc1ccc(cc1Cl)[C@H]3C[C@H]2N(C)[C@H](CC2)[C@@H]3\C=N\OC
  • InChI=1S/C16H20Cl2N2O/c1-20-11-4-6-16(20)13(9-19-21-2)12(8-11)10-3-5-14(17)15(18)7-10/h3,5,7,9,11-13,16H,4,6,8H2,1-2H3/b19-9+/t11-,12+,13+,16+/m0/s1 checkY
  • Key:NRLIFEGHTNUYFL-QJDHNRDASA-N checkY
 ☒NcheckY (what is this?)  (verify)

Brasofensine (NS-2214, BMS-204756) is a

Bristol-Myers Squibb and defunct company NeuroSearch for the treatment of Parkinson's and Alzheimer's diseases
.

History

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]

Pharmacology

In

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 after in 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 the substantia nigra brain region.

Metabolism and distribution

Brasofensine is not particularly stable and is readily metabolized. It was studied in humans in doses ranging from 2-50 mg.

radiolabeling studies using 14C, most (~90%) of the 14C was detected in the urine of humans, whereas for rats as much as 80% of the 14C was in their feces.[6]

The

epimerization at 2-position of the tropane ring, but rather involved the E/Z-isomerization of the imine (i.e. "methyl-aldoxime").[6] It was believed that this process occurs in 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 Zhu et al.,

GC-MS
. Instead, the breakdown products were N-demethylated metabolites.

References

  1. PMID 11249705
    .
  2. ^ "Brasofensine". DrugBank. 2007. Retrieved 16 March 2023.
  3. S2CID 46483126
    .
  4. S2CID 21429193
    .
  5. PMID 17017960
    .
  6. ^
    S2CID 2387909
    .
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