Design, Synthesis, and Evaluation of Prodrugs of Ertapenem

作者：Singh Sheo B^*; Rindgen Diane; Bradley Prudence; Cama Lovji; Sun Wanying; Hafey Michael J; Suzuki Takao; Wang Nengxue; Wu Hao; Zhang Basheng; Wang Li; Ji Chongmin; Yu Hongshi; Soll Richard; Olsen David B; Meinke Peter T; Nicoll Griffith Deborah A

来源：ACS Medicinal Chemistry Letters, 2013, 4(8): 715-719.

DOI：10.1021/ml400092n

• Ertapenem
• carbapenem
• antibiotics
• prodrugs
• ertapenem diethyl ester
• intraduodenal dosing
• ertapenem bis-pivoxyl
• ertapenem bis-lactone

Carbapenems are intravenous lifesaving hospital antibiotics. Once patients leave the hospital, they are sent home with antibiotics other than carbapenems since they cannot be administered orally due to lack of oral absorption primarily because of very highly polarity. A prodrug approach is a bona fide strategy to improve oral absorption of compounds. Design and synthesis, in vitro and in vivo evaluation of diversified prodrugs of ertapenem, one of the only once daily dosed carbapenems is described. Many of the prodrugs prepared for evaluation are rapidly hydrolyzed in rat plasma. Only bis-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (medoxomil) ester prodrug was rapidly hydrolyzed in most of the plasmas including rat, human, dog, and monkey. Although the rate of conversion of ertapenem diethyl ester prodrug (6) was slow in in vitro plasma hydrolysis, it showed the best in vivo pharmacokinetic profile in dog by an intraduodenal dosing giving >31% total oral absorption.

• 出版日期2013-8