Design, Synthesis, Structure-Function Relationship, Bioconversion, and Pharmacokinetic Evaluation of Ertapenem Prodrugs
Singh, SB; Rindgen, D; Bradley, P; Suzuki, T; Wang, N; Wu, Hao; Zhang, B; Wang, Li; Ji, C; Yu, H; Soll, RM; Olsen, DB; Meinke, PT; Nicoll-Griffith, DA
| HERO ID | 2795546 |
|---|---|
| In Press | No |
| Year | 2014 |
| Title | Design, Synthesis, Structure-Function Relationship, Bioconversion, and Pharmacokinetic Evaluation of Ertapenem Prodrugs |
| Authors | Singh, SB; Rindgen, D; Bradley, P; Suzuki, T; Wang, N; Wu, Hao; Zhang, B; Wang, Li; Ji, C; Yu, H; Soll, RM; Olsen, DB; Meinke, PT; Nicoll-Griffith, DA |
| Journal | Journal of Medicinal Chemistry |
| Volume | 57 |
| Issue | 20 |
| Page Numbers | 8421-8444 |
| 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. © 2014 American Chemical Society. |
| Doi | 10.1021/jm500879a |
| Pmid | 25265501 |
| Wosid | WOS:000343740700016 |
| Url | http://pubs.acs.org/doi/10.1021/jm500879a |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |
| Keyword | ertapenem; ertapenem bis 1 (pivaloyloxy)ethyl ester; ertapenem bis acetoxymethyl ester; ertapenem bis(5 methyl 2 oxo 1,3 dioxol 4yl)methyl ester; ertapenem bis(isobutanoyloxy)methyl ester; ertapenem bis(pivaloyloxy)methyl ester; ertapenem bis(propionyloxy)methyl ester; ertapenem bis[(2 ethylbutanoyl)oxy]methyl ester; ertapenem bis[(cyclohexanecarbonyl)oxy]methyl ester; ertapenem bis[(cyclohexylcarbonyl)oxy]methyl ester; ertapenem bis[(ethoxycarbonyl)oxy]methyl ester; ertapenem bis[(isopropoxycarbonyl)oxy]methyl ester; ertapenem bis[(methoxycarbonyl)oxy]methyl ester; ertapenem bis[(tert butoxycarbonyl)oxy]methyl ester; ertapenem c 3 methyl 2 ethylbutanoate sodium salt; ertapenem c 3 methyl acetate carbonate sodium salt; ertapenem c 3 methyl cycloxexyl carbonate sodium salt; ertapenem c 3 methyl isobutyratesodium salt; ertapenem c 3 methyl pivalate; ertapenem c 3 methyl propionate carbonate sodium salt; ertapenem c 3 sodium carboxyl (isobutyloxy) methylbenzoate; ertapenem c 3 sodium carboxyl methyl pivalate; ertapenem c 3 sodium carboxyl(4 methyl 5 methyl 1,3 dioxol 2 one)benzoate; ertapenem c 3 [(cyclohexanecarbonyl)oxy]methyl ester sodium salt; ertapenem c 3 [(isopropoxycarbonyl)oxy]methyl ester sodium salt; ertapenem c 3 [(tert butylcarbonyl)oxy]methyl ester sodium salt; ertapenem diisopropyl ester; n allyloxycarbonyl ertapenem; prodrug; unclassified drug; unindexed drug; beta lactam; ertapenem; ester; prodrug; animal experiment; Article; controlled study; drug absorption; drug accumulation; drug design; drug hydrolysis; drug metabolism; drug screening; drug stability; drug synthesis; drug transformation; gastrointestinal tract; male; nonhuman; rat; simulation; structure activity relation; animal; chemistry; dog; human; hydrolysis; Sprague Dawley rat; synthesis; Animals; beta-Lactams; Chemistry Techniques, Synthetic; Dogs; Drug Design; Drug Stability; Esters; Humans; Hydrolysis; Male; Prodrugs; Rats, Sprague-Dawley; Structure-Activity Relationship |