1-(9,9-Dibutyl-9H-fluoren-2-yl)-2-methyl-2-morpholin-4-yl-propan-1-one

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Objective of study:

absorption

bioaccessibility (or bioavailability)

distribution

excretion

metabolism

toxicokinetics

Test guideline

Qualifier:

according to guideline

Guideline:

other: ACD/ADME and Discovery Studio

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-(9,9-dibutyl-9H-fluoren-2-yl)-2-methyl-2-(morpholin-4-yl)propan-1-one

EC Number:

819-558-9

Cas Number:

2020359-04-8

Molecular formula:

C29H39NO2

IUPAC Name:

1-(9,9-dibutyl-9H-fluoren-2-yl)-2-methyl-2-(morpholin-4-yl)propan-1-one

Test material form:

solid: particulate/powder

Details on test material:

a off-white powdery solid, without irritating odor

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Maximum passive absorption: 100%;
Transcellular route: 100%;
Paracellular route: 0%.
Human Jejunum Scale (pH 6.5): 6.89*10-4 cm/s;
Absorption rate: ka = 0.047 min-1.
Caco-2 (pH7.4, rpm 500) to predict cell membrane permeability using Caco-2 model;
Pe: 6110-6 cm/s;
Transcellular route: 100%;
Paracellular route: 0%.
The predicted data from ACD/ADME-Absorption module indicated that the compound 1-(9,9-dibutyl-9H-fluoren-2-yl)-2-methyl-2-morpholinopropan-1-one could be absorbed in small intestine by passive absorption mainly. On the other hand, the compound may have a very low absorption rate, since it showed a very poor water solubility, a high molecular weight, and a large molecular volume.

Details on distribution in tissues:

Plasma Protein Binding Ratio (PPB%): 98%, RI=0.56.
LogKaHSA: 5.52. The parameter represents the binding constant between compound and human serum albumin (HSA). RI=0.40.
Normally, the binding rate more than 95% means a high binding rate on plasma protein, 90% to 95% for a moderate binding rate, and less than 90% for a low binding rate. ACD/ADME-Distribution model indicated that the compound 1-(9,9-dibutyl-9H-fluoren-2-yl)-2-methyl-2-morpholinopropan-1-one may bind with plasma protein in vivo with a high binding ratio more than 95% but less than 99%. In the meantime, this compound would bind to the lipoprotein but not with the albumin, since serum protein prefers a weakly-acidic compound.

Details on excretion:

1-(9,9-dibutyl-9H-fluoren-2-yl)-2-methyl-2-morpholino-propan-1-one could be metabolized into phenolic compounds or glucoside metabolites. These metabolites with increased water-solubility may be excreted in the urine. Furthermore, 1-(9,9-dibutyl-9H-fluoren-2-yl)-2-methyl-2-morpholino-propan-1-one may also be directly excreted via the urine or feces, since it was predicted to have a very low absorption rate in intestine above. In fact, fluorene was reported to be found in the urine.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

1-(9,9-dibutyl-9H-fluoren-2-yl)-2-methyl-2-morpholinopropan-1-onehave the condensed ring offluorene.Therefore, it is rationally predicted that this compound could be metabolized into phenolic metabolites, for instance, 1-(9,9-dibutyl-8-hydroxy-9H-fluoren-2-yl)-2-methyl-2-morpholino-propan-1-one(Figure 3B). The phenolic metabolites could be metabolized into glucoside compound for further increasing water-solubility.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Oral Bioavailability: 30%ACD/ADME-Oral-Bioavailability model predicated that 1-(9,9-dibutyl-9H-fluoren-2-yl)-2-methyl-2-morpholinopropan-1-one would possess amoderate oral bioavailability between 30% and 70% with a relatively-high reliability. Although the compound could be absorbed in small intestine, it was predicted to have a moderate oral bioavailability on the reason of its high logP value, big volume, and high molecular weight.

Any other information on results incl. tables

LogPS: -1.4. This parameter represents the speed of passing BBB. The predicted value is larger, the rate is faster. 

LogBB: 0.60. This parameter represents the ratio of compound between brain and blood under the steady state conditions. The predicted value is greater, the amount in brain is more. As reported, a compound with a LogBB value larger than 0.33 may possess high BBB permeability, and the LogBB value less than -0.1 indicates the compounds are difficult to pass the BBB.This compoundwas predicted to have a LogBB value more than 0.33, suggesting a high BBB permeability.

Log (PS*fu, brain): -3.7. This parameter represents blood-brain equilibrium constant. The estimated data indicated this compound could distribute in brain with a relatively high amount.

Normally, it was acknowledged that a compound exhibiting the LogP value more than 3 and the M.W. less than 450 would be relatively easy to pass the BBB. As it known, the compound 1-(9,9-dibutyl-9H-fluoren-2-yl)-2-methyl-2-morpholino-propan-1-one has the molecular weight of 433.64 and LogPof 6.5, so it would be rational to predict the compound to pass the BBB easily and to distribute in the brain.

The ACD/ADME software package predicted compound1-(9,9-dibutyl-9H-fluoren-2-yl)-2-methyl-2-morpholinopropan-1-one may be an inhibitor of P-gp. Actually, a compound with a molecular weight more than 400 and logP higher than 3.00 may bind on P-gp to block its biological functions.

Non-Inhibitor of CYP450

The ACD/ADME prediction indicated that the compound would not be an inhibitor of CYP450. In fact, the similar compoundFluorene(Similar Coefficient: 0.68, Figure 2) is not an inhibitor and could be metabolized by corresponding enzyme.It is rationally predicted that1-(9,9-dibutyl-9H-fluoren-2-yl)-2-methyl-2-morpholino-propan-1-one would not be an inhibitor of CYP450, since the compound contain a structure feature of fluorenyl ring.

DS/ADMET predicted ADMET_AlogP98 of 0.675 and level of 2. It suggested that the binding ratio on plasma proteins is more than 95%. As like ACD/ADME-Distributionpredictions, DS/ADMET also suggested that predicted compound could bind with plasma protein in a relatively low level.

Applicant's summary and conclusion

Conclusions:

In summary, both ACD/ADME and DS/ADMET, respectively, were applied to predict TK properties of 1-(9,9-dibutyl-9H-fluoren-2-yl)-2-methyl-2-morpholino-propan-1-one in this report. According to the prediction models estimated data from two different ADME prediction packages in combination with reported experimental data of the similar compound Fluorene, it was predicted that 1-(9,9-dibutyl-9H-fluoren-2-yl)-2-methyl-2-morpholinopropan-1-one could be absorbed in small intestine with a very low absorption rate.The compound could pass the BBB easily on the reason of its suitable logP (>3) and molecular weight (<450). The compound would have moderate oral bioavailability between 30% and 70%. Furthermore, it could bind with blood plasma protein with a high ratio more than 95% but less than 99%.The compound might be an inhibitor of P-gp because of its logP more than 3 and molecular weight bigger than 400. Moreover, 1-(9,9-dibutyl-9H-fluoren-2-yl)-2-methyl-2-morpholinopropan-1-one would not be an inhibitor of CYP450, and it could be transferred in vivo into phenolic metabolites by phase I metabolic enzymes and even further glucoside metabolites by phase II metabolic enzymes. These metabolites with increased water solubility may excreted via the urine. In addition, 1-(9,9-dibutyl-8-hydroxy-9H-fluoren-2-yl)-2-methyl-2-morpholinopropan-1-one might also be directly excreted via the urine or feces, since it was predicted to have a very low absorption rate in intestine.