Design, Synthesis, Structure鈥揊unction Relationship, Bioconversion, and Pharmacokinetic Evaluation of Ertapenem Prodrugs

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• 作者：Sheo B. Singh ; Diane Rindgen ; Prudence Bradley ; Takao Suzuki ; Nengxue Wang ; Hao Wu ; Basheng Zhang ; Li Wang ; Chongmin Ji ; Hongshi Yu ; Richard M. Soll ; David B. Olsen ; Peter T. Meinke ; Deborah A. Nicoll-Griffith
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 23, 2014
• 年：2014
• 卷：57
• 期：20
• 页码：8421-8444
• 全文大小：1007K
• ISSN：1520-4804

文摘

Described here are synthesis and biological evaluations of diversified groups of over 57 ertapenem prodrugs which include alkyl, methylenedioxy, carbonate, cyclic carbonate, carbamate esters, and esters containing active transport groups (e.g., carboxyl, amino acid, fatty acids, cholesterol) and macrocyclic lactones linking the two carboxyl groups. Many of the prodrugs were rapidly hydrolyzed in rat plasma but not in human plasma and were stable in simulated gastrointestinal fluid. The diethyl ester prodrug showed the best total absorption (>30%) by intredeudenal dosing in dogs, which could potentially be improved by formulation development. However, its slow rate of the hydrolysis to ertapenem also led to the presence of large amounts of circulating monoester metabolites, which pose significant development challenges. This study also suggests that the size of susbtituents at C-2 of carbapenem (e.g., benzoic acid of ertapenem) has significant impact on the absorption and the hydrolysis of the prodrugs.