Current Status of Oral Carbapenem Development

Kumagai, Toshio; Tamai, Satoshi; Abé, Takao; Hikda, Muneo

doi:10.2174/1568012023355018

Cited by 27 publications

(14 citation statements)

References 63 publications

(95 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, their basic group, which is essential for anti-bacterial activities against P. aeruginosa, 10 is also considered to limit their oral absorption. Although some newly synthesized chemically and biologically stable carbapenems lacking a basic group were reported, 11,12 no compounds have been successfully developed. Recently, tebipenem, showing high bioavailability and high activity against penicillinresistant S. pneumoniae and b-lactamase-negative ampicillin-resistant H. influenzae, was approved in Japan for pediatric otitis media, rhinitis …”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2011

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

View full text Add to dashboard Cite

show abstract

“…shows pharmacokinetic parameters of 4 after dosing 5 to mice, dogs, monkeys and humans. Especially in humans, the prodrug ester 5 showed a high Cmax and high urine excretion level of the active metabolite 4 [18]. The cumulative urinary recoveries of 4 were in the range of 65 to 79% (average: 72%) when 5 was administered orally to healthy male volunteers at a dose corresponding to 100 mg of 4.…”

Section: Biological Propertiesmentioning

confidence: 99%

Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem, L-084

et al. 2006

Self Cite

View full text Add to dashboard Cite

show abstract

“…Most carbapenems are available only intravenously up to now, because they are unstable, especially in gastric juice, but also in more alkaline intestinal pH conditions [52]. Carbapenems maintain antibacterial efficacy against the vast majority of ␤-lactamase-producing organisms.…”

Section: Carbapenemsmentioning

confidence: 99%