Synthesis and evaluation of carbamate prodrugs of a phenolic compound.
A series of carbamates of the phenolic compound 1 were prepared and evaluated in vivo as its prodrug. Each carbamate was orally administered to rats, and plasma concentrations of the parent compound 1 were measured with the passage of time. We judged which carbamate was suitable for the prodrug of 1 from both the AUC value of 1 and absence of the carbamate in plasma. The AUC value of 1 after oral administration of 2b was approximately 40-fold higher than that for an administration of 1, and the bioconversion from 2b to 1 was excellent. As a whole, di-substituted carbamates resulted in higher plasma concentrations of 1 than did mono-substituted ones. However di-substituted carbamates were almost always detected in plasma. As a result, we found that the ethycarbamoyl derivative 2b demonstrates the best prodrug property in this series.
Igarashi
Yasushi
Y
R&D Division, Tsumura & Co., Ibaraki, Japan. igarashi_yasushi@mail.tsumura.co.jp
Yanagisawa
Erika
E
Ohshima
Toshihiro
T
Takeda
Shuichi
S
Aburada
Masaki
M
Miyamoto
Ken-ichi
K
D000284:Administration, Oral; D000818:Animals; D001711:Biotransformation / Q000187:drug effects* / Q000502:physiology; D002219:Carbamates / Q000138:chemical synthesis*; D004355:Drug Stability; D008956:Models, Chemical; D010636:Phenols / Q000138:chemical synthesis* / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats
D002219:Carbamates; D010636:Phenols; D011355:Prodrugs