Phenolic Esters of O-Desmethylvenlafaxine with Improved Oral Bioavailability and Brain Uptake
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Pharmacokinetic (PK) Studies in Rat
Compd. | Clog P | Cmax | Tmax | t1/2 | AUC0-t | AUC0-∞ | MRT | F |
---|---|---|---|---|---|---|---|---|
μg/L | h | h | μg/L × h | μg/L × h | h | % | ||
ODV | 3.3 | 66.6 ± 14.6 | 1.25 ± 1.06 | 4.14 ± 1.21 | 219 ± 56 | 222 ± 59 | 6.03 ± 2.82 | 100 |
1a | 4.8 | 7.67 ± 1.21 | 1.50 ± 0.71 | 2.13 ± 0.83 | 41.1 ± 3.8 | 41.1 ± 3.7 | 4.70 ± 0.47 | 18.7 |
1b | 5.4 | 18.2 ± 3.4 | 1.50 ± 0.24 | 3.95 ± 1.84 | 152 ± 15 | 156 ± 20 | 6.99 ± 1.40 | 69.5 |
1c | 5.2 | 98.8 ± 14.5 | 0.50 ± 0.12 | 5.47 ± 1.50 | 278 ± 86 | 293 ± 103 | 4.81 ± 2.06 | 127 |
1d | 6.7 | 33.3 ± 18.0 | 0.92 ± 0.83 | 6.40 ± 5.30 | 222 ± 114 | 246 ± 148 | 6.31 ± 0.44 | 101 |
1e | 5.9 | 118 ± 16 | 0.33 ± 0.04 | 2.39 ± 0.15 | 321 ± 83 | 321 ± 93 | 4.37 ± 1.39 | 146 |
1f | 5.6 | 47.0 ± 13.4 | 2.00 ± 1.41 | 4.61 ± 2.28 | 216 ± 89 | 220 ± 87 | 4.53 ± 1.96 | 98.4 |
1g | 4.2 | 9.36 ± 3.60 | 0.58 ± 0.59 | 1.65 ± 0.11 | 29.4 ± 0.2 | 29.4 ± 0.2 | 4.14 ± 0.10 | 13.4 |
1h | 4.9 | 15.7 ± 4.6 | 0.50 ± 0.07 | 2.53 ± 1.65 | 58.7 ± 23.9 | 58.9 ± 23.6 | 4.92 ± 1.14 | 26.8 |
1i | 4.0 | 10.5 ± 2.7 | 0.50 ± 0.12 | 1.19 ± 0.80 | 21.3 ± 2.8 | 21.3 ± 2.8 | 2.35 ± 0.40 | 9.73 |
1j | 6.1 | 101 ± 31 | 0.42 ± 0.09 | 2.49 ± 0.44 | 241 ± 61 | 251 ± 80 | 2.77 ± 0.80 | 110 |
1k | 5.7 | 96.3 ± 24.7 | 1.75 ± 0.35 | 4.32 ± 0.82 | 228 ± 38 | 231 ± 47 | 4.95 ± 1.85 | 104 |
1l | 5.4 | 12.4 ± 13.5 | 1.50 ± 0.71 | 8.61 ± 3.09 | 27.8 ± 23.6 | 33.9 ± 23.7 | 9.29 ± 3.43 | 12.7 |
1m | 5.4 | 30.4 ± 5.9 | 1.25 ± 0.35 | 6.35 ± 4.09 | 178 ± 60 | 197 ± 84 | 6.75 ± 1.60 | 81.3 |
1n | 5.5 | 141 ± 48 | 1.00 ± 0.58 | 8.29 ± 5.12 | 421 ± 146 | 456 ± 153 | 4.42 ± 0.74 | 192 |
1o | 5.1 | 87.7 ± 13.3 | 0.44 ± 0.10 | 9.02 ± 1.74 | 278 ± 85 | 318 ± 84 | 6.83 ± 0.73 | 127 |
2.3. Brain Uptake Studies in Rat
2.4. PK Studies of 1n and ODV in Beagle Dog
Compd. | Cmax | Tmax | t1/2 | AUC0–t | AUC0–∞ | MRT | F |
---|---|---|---|---|---|---|---|
μg/L | h | h | μg/L × h | μg/L × h | h | % | |
ODV | 7.55 ± 4.34 | 2.67 ± 0.58 | 1.55 ± 0.29 | 27.7 ± 12.1 | 27.8 ± 12.6 | 4.10 ± 0.70 | 100 |
1n | 20.8 ± 6.6 | 1.21 ± 0.61 | 3.41 ± 1.54 | 55.1 ± 17.2 | 55.5 ± 16.9 | 3.91 ± 0.76 | 199 |
3. Experimental
3.1. General
3.2. General Procedure for Synthesis of Compounds a–o
3.3. General Procedure for Synthesis of Compounds 1a–o
3.4. PK Studies in Rat
3.5. Brain Uptake Studies in Rat
3.6. PK Studies in Beagle Dog
4. Conclusions
Acknowledgments
Conflicts of Interest
References
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Zhang, Y.; Yang, Y.; Zhao, S.; Yang, Z.; Yang, H.; Fawcett, J.P.; Li, Y.; Gu, J.; Sun, T. Phenolic Esters of O-Desmethylvenlafaxine with Improved Oral Bioavailability and Brain Uptake. Molecules 2013, 18, 14920-14934. https://doi.org/10.3390/molecules181214920
Zhang Y, Yang Y, Zhao S, Yang Z, Yang H, Fawcett JP, Li Y, Gu J, Sun T. Phenolic Esters of O-Desmethylvenlafaxine with Improved Oral Bioavailability and Brain Uptake. Molecules. 2013; 18(12):14920-14934. https://doi.org/10.3390/molecules181214920
Chicago/Turabian StyleZhang, Yang, Yan Yang, Sen Zhao, Zhichao Yang, Hong Yang, J. Paul Fawcett, Youxin Li, Jingkai Gu, and Tiemin Sun. 2013. "Phenolic Esters of O-Desmethylvenlafaxine with Improved Oral Bioavailability and Brain Uptake" Molecules 18, no. 12: 14920-14934. https://doi.org/10.3390/molecules181214920