R7 (drug)

R7

Clinical data
Other names	4-Oxo-2-phenyl-4H-chromene-7,8-diyl bis(dimethylcarbamate)
Routes of administration	By mouth[1]
Legal status
Legal status	US: Investigational New Drug
Pharmacokinetic data
Bioavailability	~35% (in mice)[2]
Metabolites	Tropoflavin[1]
Elimination half-life	~3.25 hours (in mice[2]
Identifiers
IUPAC name [8-(Dimethylcarbamoyloxy)-4-oxo-2-phenylchromen-7-yl] N,N-dimethylcarbamate
CAS Number	1609067-35-7^Y
PubChem CID	73672564
UNII	2KYC4WG53K
Chemical and physical data
Formula	C21H20N2O6
Molar mass	396.399 g·mol^−1
3D model (JSmol)	Interactive image
SMILES CN(C)C(=O)OC1=C(C2=C(C=C1)C(=O)C=C(O2)C3=CC=CC=C3)OC(=O)N(C)C
InChI InChI=1S/C21H20N2O6/c1-22(2)20(25)28-16-11-10-14-15(24)12-17(13-8-6-5-7-9-13)27-18(14)19(16)29-21(26)23(3)4/h5-12H,1-4H3 Key:KHUMQRAGNPGBIE-UHFFFAOYSA-N

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.^[1][3][2] It is a structural modification and prodrug of tropoflavin (7,8-DHF) with improved potency and pharmacokinetics, namely oral bioavailability and duration.^[2]

Discovery

R7 was synthesized by the same researchers who were involved in the discovery of tropoflavin.^[2][4] A patent was filed for R7 in 2013 and was published in 2015.^[2] In 2016, it was reported to be in the preclinical stage of development.^[1][3] R7 was superseded by R13 because while R7 had a good drug profile in animals, it showed almost no conversion into tropoflavin in human liver microsomes.^[5]

Tropoflavin, a naturally occurring flavonoid, was found to act as an agonist of the TrkB with nanomolar affinity (K_d ≈ 320 nM).^[4]

Due to the presence of a vulnerable catechol group on its 2-phenyl-4H-chromene ring, tropoflavin 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.^[2] As such, tropoflavin itself is a poor candidate for clinical development as an oral medication.^[2] R7 is a derivative of tropoflavin with carbamate moieties on its hydroxyl groups, thereby protecting it from metabolism.^[2]

Pharmacokinetics

As R7 is a slightly larger molecule than tropoflavin, 72.5 mg R7 is molecularly equivalent to 50 mg tropoflavin.^[2] Relative to a roughly molecularly equivalent dose of tropoflavin, 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%.^[2] Moreover, whereas tropoflavin itself is mostly metabolized in mice within 30 minutes, tropoflavin as a metabolite was still detectable in plasma at 8 hours after administration with R7, indicating that R7 sustainably releases tropoflavin into circulation.^[2] In accordance, the terminal half-life of R7 is about 195 minutes (3.25 hours) in mice.^[2] The T_max of R7 is about 60 minutes in mice, and its C_max for a 78 mg/kg dose was 262 ng/mL, whereas that for a 50 mg/kg dose of tropoflavin was 70 ng/mL.^[2]

Animal studies

Like tropoflavin, administration of R7 has been found to activate the TrkB in vivo in the mouse brain.^[2] 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 tropoflavin.^[2] As such, R7 has shown in vivo efficacy as an agonist of the TrkB, including central activity, similarly to tropoflavin.^[2]

See also

• List of investigational antidepressants
• Tropomyosin receptor kinase B § Agonists

References

1. Liu C, Chan CB, Ye K (2016). "7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders". Translational Neurodegeneration. 5 (1): 2. doi:10.1186/s40035-015-0048-7. PMC 4702337. PMID 26740873.
2. US application 20150274692, Ye K, "7,8-Dihydoxyflavone and 7,8-substituted flavone derivatives, compositions, and methods related thereto", published 2015-10-01, assigned to Emory University. 
3. Kazim SF, Iqbal K (July 2016). "Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer's disease". Molecular Neurodegeneration. 11 (1): 50. doi:10.1186/s13024-016-0119-y. PMC 4940708. PMID 27400746.
4. Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, et al. (February 2010). "A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone". Proceedings of the National Academy of Sciences of the United States of America. 107 (6): 2687–2692. Bibcode:2010PNAS..107.2687J. doi:10.1073/pnas.0913572107. PMC 2823863. PMID 20133810.
5. 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". Proceedings of the National Academy of Sciences of the United States of America. 115 (3): 578–583. Bibcode:2018PNAS..115..578C. doi:10.1073/pnas.1718683115. PMC 5777001. PMID 29295929.

External links

• 7,8-Dihydoxyflavone and 7,8-substituted flavone derivatives, compositions, and methods related thereto (US 20150274692 A1)