title: Design, synthesis, structure-function relationship, bioconversion, and pharmacokinetic evaluation of ertapenem prodrugs.
abstract: 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.
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.forename: Diane
authors.initials: D
authors.lastname: Rindgen
authors.forename: Prudence
authors.initials: P
authors.lastname: Bradley
authors.forename: Takao
authors.initials: T
authors.lastname: Suzuki
authors.forename: Nengxue
authors.initials: N
authors.lastname: Wang
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Basheng
authors.initials: B
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Chongmin
authors.initials: C
authors.lastname: Ji
authors.forename: Hongshi
authors.initials: H
authors.lastname: Yu
authors.forename: Richard M
authors.initials: RM
authors.lastname: Soll
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nicoll-Griffith
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D004285:Dogs; D015195:Drug Design; D004355:Drug Stability; D000077727:Ertapenem; D004952:Esters / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D047090:beta-Lactams / Q000737:chemistry*
chemical_list: D004952:Esters; D011355:Prodrugs; D047090:beta-Lactams; D000077727:Ertapenem