BMS-204352 {[3S]-[+]-[5-chloro-2-methoxyphenyl]-
1,3-dihydro-3-fluoro-6-[trifluoromethyl]-2H-indol- 2-one}, a novel
fluorooxindole maxi-K channel opener, was being developed for the treatment of
stroke.
The compound is highly potent and specific for the target site of
action and has been shown to be efficacious for therapy of acute forms of
stroke after intravenous dosing in animal stroke models [1].
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| BMS-204352: 2D and 3D Structure |
The European Medicines Agency (EMA) has granted "orphan
designation" to BMS-204352, a molecule being developed by the CNRS to treat
Fragile X Syndrome, a rare genetic disease for which there exists no treatment.
Common Name: BMS-204352
Synonyms: BMS-204352; BMS204352; BMS 204352; Flindokalner
IUPAC Name: (3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one
CAS Number:
SMILES:
Mechanism of Action: Maxi-K Channel Opener
Indication: Treatment of Strokes; Treatment of Fragile X Syndrome
Development Stage: Phase I
Company: Bristol Meyer Squibb/CNRS
Fragile X syndrome is a rare disorder produced by mutations in the Fragile X mental retardation 1 gene, which result in abnormal neuropsychologic development. It manifests clinically with autism, intellectual disability, attention-deficit hyperactivity disorder and muscle hypotonia [3]. Fragile X Syndrome (FXS) is the most common cause of inherited mental deficiency and is associated with autistic features. FXS is caused by a CGG triplet expansion in the FMR1 gene resulting in the absence of its coding protein, Fragile X Mental Retardation Protein (FMRP). This mRNA-binding protein regulates both localization and translation of specific mRNAs in synaptic regions, but also controls synaptic membrane proteins activity through a translation-independent pathway. As a consequence of this synaptic disturbance, a preponderance of long, thin and tortuous dendritic spines in cortex is observed in FXS patients brain. Fmr1 knock-out (KO) mouse, a murine model of human FXS, presents both dendritic spines maturation abnormalities and many behavioral characteristics similar to human FXS, including altered social interaction, occurrence of repetitive behaviors, hyperactivity and cognitive dysfunction [4].
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| 1H NMR (Estimated) for BMS-204352 |
Fragile X syndrome is a rare disorder produced by mutations in the Fragile X mental retardation 1 gene, which result in abnormal neuropsychologic development. It manifests clinically with autism, intellectual disability, attention-deficit hyperactivity disorder and muscle hypotonia [3]. Fragile X Syndrome (FXS) is the most common cause of inherited mental deficiency and is associated with autistic features. FXS is caused by a CGG triplet expansion in the FMR1 gene resulting in the absence of its coding protein, Fragile X Mental Retardation Protein (FMRP). This mRNA-binding protein regulates both localization and translation of specific mRNAs in synaptic regions, but also controls synaptic membrane proteins activity through a translation-independent pathway. As a consequence of this synaptic disturbance, a preponderance of long, thin and tortuous dendritic spines in cortex is observed in FXS patients brain. Fmr1 knock-out (KO) mouse, a murine model of human FXS, presents both dendritic spines maturation abnormalities and many behavioral characteristics similar to human FXS, including altered social interaction, occurrence of repetitive behaviors, hyperactivity and cognitive dysfunction [4].
Recent studies have demonstrated the implication of potassium channels in FXS pathology. Among them, large-conductance Ca2+-activated K+ channels (BKCa channels, also known as BK or Maxi-K channels), activated by membrane depolarization and increased intracellular Ca2+ concentration, are of particular interest because of their control of Ca2+ concentration in neurons and regulation of neurotransmitter release such as glutamate. Several data provide convincing evidence that this channel is closely linked to behavioral and cognitive disorders. Physical mapping of balanced chromosomal aberrations revealed a KCNMA1 gene disruption in a subject with autism and intellectual deficiency. This gene haploinsufficiency induced a functional defect of BKCa channels that might contribute to neurological symptoms. In addition, a mutation in the CRBN gene, an upstream regulator of BKCa channel, has been also associated with autosomal recessive non-syndromic mental retardation.The existing therapies are focused on the alleviation of the psychiatric symptoms. More recently, compounds have been evaluated as potential therapies for this condition for ex. BMS-204352 a maxi-K channel opener [4].
References:
1. Krishna, R.; et. al. In Vitro Protein Binding Studies with BMS-204352: Lack of Protein Binding Displacement Interaction in Human Serum. Biopharm Drug Dispos 2001, 22, 41-44.
2. Jensen, B. S.; et. al. BMS-204352: a potassium channel opener developed for the treatment of stroke. CNS Drug Rev 2002 Winter, 8(4), 353-360.
3. Mclennan, Y.; et. al. Fragile x syndrome. Curr Genomics 2011, 12(3), 216-224.
4. Briault, S.; et. al. Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule. Orphanet J Rare Dis 2014, 9, 124.
5. Feng, X.; et. al. Highly Enantioselective Fluorination of Unprotected 3-Substituted Oxindoles: One-Step Synthesis of BMS 204352 (MaxiPost). J Org Chem 2012, 77(20), 9148-9155.
6. Hewawasam, P. et. al. The synthesis and characterization of BMS-204352 (MaxiPost) and related 3-fluorooxindoles as openers of maxi-K potassium channels. Bioorg Med Chem Lett 2002, 12(7), 1023-1026.
7. Cahard, D.; et. al. Enantioselective synthesis of BMS-204352 (MaxiPost™) using N-fluoroammonium salts of cinchona alkaloids (F–CA–BF4). Org Biomol Chem 2003,1, 1833-1834.
