|Other names||4-Oxo-2-phenyl-4H-chromene-7,8-diyl bis(dimethylcarbamate)|
|Bioavailability||~35% (in mice)|
|Elimination half-life||~3.25 hours (in mice|
|Chemical and physical data|
|Molar mass||396.399 g/mol g·mol−1|
|3D model (JSmol)|
R7 is a small-molecule flavonoid and orally active, potent, and selective agonist of the tropomyosin receptor kinase B (TrkB) – the main signaling receptor for the neurotrophin brain-derived neurotrophic factor (BDNF) – which is under development for the treatment of Alzheimer's disease. It is a structural modification and prodrug of 7,8-dihydroxyflavone (7,8-DHF) with improved potency and pharmacokinetics, namely oral bioavailability and duration. R7 was synthesized by the same researchers who were involved in the discovery of 7,8-DHF. A patent was filed for R7 in 2013 and was published in 2015. In 2016, it was reported to be in the preclinical stage of development. R7 was superseded by R13 because while R7 had a good drug profile in animals, it showed almost no conversion into 7,8-DHF in human liver microsomes.
In 2010, 7,8-DHF, a naturally occurring flavonoid, was found to act as an agonist of the TrkB with nanomolar affinity (Kd ≈ 320 nM). Subsequently, 7,8-DHF demonstrated robust efficacy in animal models of Alzheimer's disease and a variety of other conditions, making it a highly promising potential therapeutic agent. Due to the presence of a vulnerable catechol group on its 2-phenyl-4H-chromene ring, 7,8-DHF is extensively conjugated via glucuronidation, sulfation, and methylation during first-pass metabolism in the liver and has a poor oral bioavailability of only 5% in mice upon oral administration. As such, 7,8-DHF itself is a poor candidate for clinical development as an oral medication. R7 is a derivative of 7,8-DHF with carbamate moieties on its hydroxyl groups, thereby protecting it from metabolism.
As R7 is a slightly larger molecule than 7,8-DHF, 72.5 mg R7 is molecularly equivalent to 50 mg 7,8-DHF. Relative to a roughly molecularly equivalent dose of 7,8-DHF, the area-under-curve levels of R7 were found to be 7.2-fold higher upon oral administration to mice, and R7 hence has a greatly improved oral bioavailability in mice of approximately 35%. Moreover, whereas 7,8-DHF itself is mostly metabolized in mice within 30 minutes, 7,8-DHF was still detectable in plasma at 8 hours after administration with R7, indicating that R7 sustainably releases 7,8-DHF into circulation. In accordance, the terminal half-life of R7 is about 195 minutes (3.25 hours) in mice. The Tmax of R7 is about 60 minutes in mice, and its Cmax for a 78 mg/kg dose was 262 ng/mL, whereas that for a 50 mg/kg dose of 7,8-DHF was 70 ng/mL.
Like 7,8-DHF, administration of R7 has been found to activate the TrkB in vivo in the mouse brain. Moreover, R7 was found to potently activate the TrkB and the downstream Akt signaling pathway upon oral administration, an action that was tightly correlated with plasma concentrations of 7,8-DHF. As such, R7 has shown in vivo efficacy as an agonist of the TrkB, including central activity, similarly to 7,8-DHF.
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- US application 20150274692, Keqiang Ye, "7,8-Dihydoxyflavone and 7,8-substituted flavone derivatives, compositions, and methods related thereto", published 2015-10-01, assigned to Emory University
- Kazim, Syed Faraz; Iqbal, Khalid (2016). "Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer's disease". Molecular Neurodegeneration. 11 (1). doi:10.1186/s13024-016-0119-y. ISSN 1750-1326. PMC 4940708.
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- Chen C, Wang Z, Zhang Z, Liu X, Kang SS, Zhang Y, Ye K (January 2018). "The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer's disease". Proc. Natl. Acad. Sci. U.S.A. 115 (3): 578–583. doi:10.1073/pnas.1718683115. PMID 29295929.
- 7,8-Dihydoxyflavone and 7,8-substituted flavone derivatives, compositions, and methods related thereto (US 20150274692 A1)