Design, synthesis, structure function relationship, bioconversion and pharmacokinetic evaluation of ertapenem prodrugs.

Design, synthesis, structure function relationship, bioconversion and pharmacokinetic evaluation of ertapenem prodrugs.

J Med Chem. 2014 Sep 29;

Authors: Singh SB, Rindgen D, Bradley P, Suzuki T, Wang N, Wu H, Zhang B, Wang L, Ji C, Yu H, Soll RM, Olsen DB, Meinke PT, Nicoll-Griffith DA

Abstract
Abstract Described here are synthesis and biological evaluations of diversified groups of over fifty seven 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 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.

PMID: 25265501 [PubMed - as supplied by publisher]