title: Design, synthesis, and evaluation of prodrugs of ertapenem.
abstract: 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.
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Diane
authors.initials: D
authors.lastname: Rindgen
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Prudence
authors.initials: P
authors.lastname: Bradley
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Lovji
authors.initials: L
authors.lastname: Cama
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Wanying
authors.initials: W
authors.lastname: Sun
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hafey
authors.affiliation: Wuxi Apptec , Shanghai, People Republic of China.
authors.forename: Takao
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Wuxi Apptec , Shanghai, People Republic of China.
authors.forename: Nengxue
authors.initials: N
authors.lastname: Wang
authors.affiliation: Wuxi Apptec , Shanghai, People Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Wuxi Apptec , Shanghai, People Republic of China.
authors.forename: Basheng
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Wuxi Apptec , Shanghai, People Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Wuxi Apptec , Shanghai, People Republic of China.
authors.forename: Chongmin
authors.initials: C
authors.lastname: Ji
authors.affiliation: Wuxi Apptec , Shanghai, People Republic of China.
authors.forename: Hongshi
authors.initials: H
authors.lastname: Yu
authors.affiliation: Wuxi Apptec , Shanghai, People Republic of China.
authors.forename: Richard
authors.initials: R
authors.lastname: Soll
authors.affiliation: Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nicoll-Griffith
keywords: Ertapenem; antibiotics; carbapenem; ertapenem bis-lactone; ertapenem bis-pivoxyl; ertapenem diethyl ester; intraduodenal dosing; prodrugs