1446142-22-8Relevant academic research and scientific papers
Design, synthesis, and evaluation of prodrugs of ertapenem
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.
, p. 715 - 719 (2013)
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.
Design, synthesis, structure-function relationship, bioconversion, and pharmacokinetic evaluation of ertapenem prodrugs
Singh, Sheo B.,Rindgen, Diane,Bradley, Prudence,Suzuki, Takao,Wang, Nengxue,Wu, Hao,Zhang, Basheng,Wang, Li,Ji, Chongmin,Yu, Hongshi,Soll, Richard M.,Olsen, David B.,Meinke, Peter T.,Nicoll-Griffith, Deborah A.
, p. 8421 - 8444 (2014/12/11)
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.
