Assay Data pulled from US Patent. Potency is expressed in EC50 (µM)


Initial comparison of the patent table above with EC50 values from this study (table below) eliminated several options, leading to the identification of Example 5 as the closest match to ACD856. This assessment, while preliminary, provides a strong indication of the compound's identity, though further verification is necessary for absolute confirmation.



After sifting between patent documents, the same latency graph appears in nearly every patent they have submitted, and it conveniently only references Example 5.

…this matches the in-vivo behavioral studies of ACD856 


 “ACD856 was administered s.c. for 4 consecutive days at 0.1 mg/kg or as a single s.c. dose at 0.1, 0.3, or 1 mg/kg 60 min prior to the experiment, in combination with scopolamine (0.3 mg/kg, s.c.) ACD856 reversed scopolamine-induced memory impairment at the indicated doses (a). * p < 0.05 or **** p < 0.0001 for scopolamine treated animals vs. the control group or ACD856-treated animals. Mice were injected for five days with a single dose of ACD856 (1 mg/kg, s.c.) per day or with a single dose of 10 mg/kg ketamine seven days prior to swimming session.”

They attempted to be discreet in their Patent Approach

  • Removed 4x0.1 and 1x1 dosages from study
  • Applied stricter p-value in in-vivo studies

Graph and P-value Correlations:

  1. Control vs. ScopolamineBoth graphs: Significant differences
  2. Scopolamine vs. Moderate DoseACD856 (0.1 mg/kg), Example 5 (0.3 mg/kg)
  3. Scopolamine vs. Higher DoseACD856 (0.3 mg/kg), Example 5 (1 mg/kg)

.

We calculated the molecular weight by extrapolating pharmacokinetic data from this study. This approach provided a method to verify and cross-reference the compound's identity.

From Plasma (Subcutaneous Administration)

Given:

  • 3550 nmol/L * (MW in g/mol) = 1375 μg/L
  • 3.55 μmol/L * (MW in g/mol) = 1375 μg/L

Calculation:

MW = 1375 μg/L / 3.55 μmol/L = 387.32 g/mol

From Plasma (Oral Administration)

Given:

  • 65,960 nM = 25,500 ng/mL
  • 65.96 μmol/L * (MW in g/mol) = 25,500 μg/L

Calculation:

  • MW = 25,500 μg/L / 65.96 μmol/L = 386.60 g/mol


From here it only made sense to revisit the patents to determine the molecular weight for not only Example 5 but all examples 1-78. Luckily, the European patent documents revealed structures for all 78, allowing us to derive the theoretical molecular weight.

Theoretical Calculation for Example 5

  • C: 12.01 g/mol
  • H: 1.01 g/mol
  • N: 14.01 g/mol
  • O: 16.00 g/mol
  • Composition:
  • C: 22 × 12.01 = 264.22 g/mol
  • H: 17 × 1.01 = 17.17 g/mol
  • N: 3 × 14.01 = 42.03 g/mol
  • O: 4 × 16.00 = 64.00 g/mol
  • Total molecular weight = 387.42 g/mo

Very promising. After calculating the theoretical molecular weight, we uncovered more information in the patents that allowed us to swiftly determine the molecular weight for all examples 1-78. The molecular weight for each structure was provided via mass spectrometry data, allowing us to easily acquire molecular weight, potentially providing the definitive evidence needed to confirm that Example 5 is indeed ACD856. Interestingly, this level of detail provided is required in European patents (disclosure requirements for companies publishing patents in Europe (EPC)) Which are not detailed in other countries' patents.

We analyzed the molecular weight for all compounds provided in published patents for ACD856. Example 5 has the exact molecular weight. 2 others also shared molecular weight, but we went on to eliminate example 6 as the EC50 is way off compared to ACD856. See link attachment below for findings and rationale.

 https://acd856weight.tiiny.site/

For more confidence in our findings, we did a final separate analysis of ACD856, based on ALL Patent Information and every study referencing ACD856. Focusing entirely on structure and therapeutic effects cross referencing all patents.

Relevant Patents and Compounds:

Patent EP 3 759 088 B1 describes triazinane-2,4,6-trione derivatives, particularly focusing on compounds that modulate Trk receptors, which are used for treating neurodegenerative and psychiatric disorders. The patent lists several compounds, we reduced the relevant structures to:

Example 5: 1-(3-methyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

Example 70: 1-(2-methyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione

Synthesis of ALL Patents:

We have the structural framework and substituent variations for triazinetrione compounds, with the most relevant compounds specifically highlighting their potential in treating neurotrophic signaling disorders such as Alzheimer's disease which ACD856 is being targeted for. Findings show:

  1. Core Structure:1,3,5-triazinane-2,4,6-trione
  2. Phenoxy Group:4-phenoxy substituent on the phenyl ring
  3. Methyl Group:3-methyl substituent on the phenyl ring
  4. Phenyl Group:Phenyl group at the 3-position of the triazinane ring
  5. Pharmacological Profile:Positive allosteric modulator of Trk receptors (TrkA, TrkB)
  6. Therapeutic Use:Targets neurodegenerative diseases

This leaves us with  Example 5.

  1. It has the correct 3-methyl-4-phenoxy arrangement on the phenyl ring.
  2. It has a phenyl group at the 3-position of the triazinane ring.
  3. It maintains the core 1,3,5-triazinane-2,4,6-trione structure.

With high confidence, we can conclude the candidate for ACD856 is 1-(3-methyl-4-phenoxyphenyl)-3-phenyl-1,3,5-triazinane-2,4,6-trione