title: 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 β-lactamase-negative ampicillin-resistant H. influenzae.
authors.affiliation: Research Laboratories, Kyoto Pharmaceutical Industries, Nakagyo-ku, Kyoto, Japan.
authors.forename: Shunkichi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsui
authors.forename: Masayasu
authors.initials: M
authors.lastname: Kasai
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kunishiro
authors.forename: Nobuharu
authors.initials: N
authors.lastname: Kakeya
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shirahase
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism; D015780:Carbapenems / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D000077731:Meropenem; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D013845:Thienamycins / Q000378:metabolism*
chemical_list: C558363:1-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; D000900:Anti-Bacterial Agents; D015780:Carbapenems; D011355:Prodrugs; D011759:Pyrrolidines; D013845:Thienamycins; C558362: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; D000077731:Meropenem