Novel prodrugs of meropenem with two lipophilic promoieties: synthesis and pharmacokinetics

Abstract

To improve the oral absorption of meropenem (MEPM), we synthesized and evaluated a series of its double-promoiety prodrugs, in which lipophilic promoieties were introduced into carboxyl and pyrrolidinyl groups. Among these prodrugs, pivaloyloxymethyl (1R,5S,6S)-2-[(3S,5S)-5-(N,N-dimethylcarbamoyl)-1-(isobutyryloxymethyloxycarbonyl)pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (4) and 1-ethylpropyloxycarbonyloxymethyl (1R,5S,6S)-2-[(3S,5S)-5-(N,N-dimethylcarbamoyl)-1-(isobutyryloxymethyloxycarbonyl)pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (8) were chosen for further evaluation. Compounds 4 and 8 were well absorbed after oral administration to rats and beagles (bioavailability 18.2-38.4%), and expected to show potent therapeutic efficacy in patients infected with various pathogens, such as penicillin-resistant S. pneumoniae and b-lactamase-negative ampicillin-resistant H. influenzae. The Journal of Antibiotics (2011) 64, 233-242; doi:10.1038/ja.2010; published online 12 January 2011Keywords: carbapenem; double-promoiety prodrug; meropenem; single-promoiety prodrug INTRODUCTIONCarbapenems are the most potent class of b-lactam antibiotics, which have a broad spectrum of potent antibacterial activities against Grampositive and Gram-negative organisms, including P. aeruginosa. 1,2 Carbapenems are stable to hydrolysis by various b-lactamase, and thus, effective against most cephalosporin-resistant microorganisms. [3][4][5] Imipenem, panipenem and meropenem (MEPM) have long been used for serious infectious diseases, including complicated urinary tract infection and complicated respiratory tract infection (Figure 1). 1 Recently, doripenem has been launched as a new potent carbapenem (Figure 1). 6 However, these are all for parenteral use only. Imipenem and panipenem are unstable chemically and to renal dehydropeptidase-I, and are thus used in combination with cilastatin and betamipron, respectively. MEPM and doripenem have a 1b-methyl group, and are stable against chemical degradation and hydrolysis by dehydropeptidase-I, 7-9 and are thus used without cilastatin or betamipron.All these parenteral carbapenems have a carboxyl group at the carbapene C-3 position, which is essential for interaction with a target protein, penicillin-binding protein, 1 and a basic group at the pyrrolidine N-1 position, which promote their invasion through D2 porin into P. aeruginosa, 10 resulting in little oral absorption because of the two ionizable groups. Many attempts to find new orally active carbapenems have been reported, 11,12 in which the basic group at the pyrrolidine N-1 position was eliminated and the carboxyl group was esterified by easily hydrolizable promoiety to increase oral absorption, but most showed very weak antibacterial activity against P. aeruginosa. Recently, tebipenem was developed in Japan and approved as a new orally active carbapenem ( Figure 1). Tebipenem showed potent activity against penicillin-resistant S. pneumoniae, b-lactamase-negat...

Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis

“…carbamate prodrugs) could be used to slow the production of meropenem and this strategy has been explored previously. 18 …”

“…Meropenem is a highly polar zwitterionic molecule (Log D < −2.5) 18 and unstable in aqueous conditions and must therefore be given intravenously within 3 hours following aqueous reconstitution. Aqueous degradation products are derived from β-lactam hydrolysis (major) and β-lactam dimerization (minor) via intermolecular attack of the pyrrolidine nitrogen onto the β-lactam.…”

“…24 Meropenem bis-prodrugs with a pivoxil ester attached to the carboxylate and various acyloxymethyl carbamates attached to the pyrrolidine nitrogen were reported with bioavailabilities ranging from 27.0–29.5% in the rat and 24.4–38.4% in the beagle dog. 18 Although pivoxil esters have been utilized as promoieties to improve the lipophilicity of β-lactam antibiotics, the released pivalic acid is a concern for chronic therapy such as TB. Pivalic acid enters into the branched-chained fatty acid acyl carnitine pathway and forms pivaloyl CoA, which is excreted as pivaloyl carnitine.…”

Biofunctional Hyaluronic Acid/κ-Carrageenan Injectable Hydrogels for Improved Drug Delivery and Wound Healing

“…The progression of infection in the wound microenvironment is avoided by the use of broad-spectrum antibiotics such as meropenem, which is a β-lactam antibiotic with a broad spectrum of activity. Due to its reduced oral absorption and short half-life, i.e., 0.75-1 h [26], meropenem requires multiple intravenous injections after short intervals, i.e., every 3 h after reconstitution [27]. To improve stability, bioavailability, [28], and patient compliance, a new drug-delivery system for effective meropenem delivery is required [29].…”

Dexamethasone Ibuprofen Prodrug Synthesis and Preliminary Kinetic Study

“…In 2010, Cassano et al reported the synthesis of a new 5-amino salicylic acid (5-ASA) pro-prodrug, useful in Crohn disease treatment [11]. Recently in 2011, Tanaka et al improved the oral absorption of meropenem, where they synthesized and evaluated a series of its double-promoiety prodrugs, in which lipophilic promoieties were introduced into carboxyl and pyrrolidinyl groups [12]. In the present paper we synthesized a potential prodrug of dexamethasone conjugated with ibuprofen through a spacer arm amino acid (glycine).…”