Thorberg S O, Berg S, Lundström J, Pettersson B, Wijkström A, Sanchez D, Lindberg P, Nilsson J L
Astra Alab AB, Research & Development Laboratories, Södertälje, Sweden.
J Med Chem. 1987 Nov;30(11):2008-12. doi: 10.1021/jm00394a014.
Twenty derivatives bearing substituents on the phenolic function of (-)-3-(3-hydroxyphenyl)-N-propylpiperidine [(-)-3-PPP] were synthesized and tested as prodrugs. The carbamate ester derivatives were found to be the most suitable prodrugs, and especially the 4-isopropylphenylcarbamate 20 was capable of escaping the first-pass metabolism and still generating high plasma levels of the parent compound. Four hours after an oral dose of 100 mumol/kg to rats, a plasma level of 2400 nmol/L of (-)-3-PPP was detected by an HPLC method. This was 90 times the level reached after 4 h (27 nmol/L) when (-)-3-PPP itself was given orally at the same dose.
合成了二十种在(-)-3-(3-羟基苯基)-N-丙基哌啶[(-)-3-PPP]酚羟基上带有取代基的衍生物，并作为前药进行了测试。发现氨基甲酸酯衍生物是最合适的前药，尤其是4-异丙基苯基氨基甲酸酯20能够避免首过代谢，并且仍能产生高血浆水平的母体化合物。给大鼠口服100 μmol/kg剂量4小时后，通过高效液相色谱法检测到(-)-3-PPP的血浆水平为2400 nmol/L。这是相同剂量口服(-)-3-PPP本身4小时后达到的水平（27 nmol/L）的90倍。
