title: Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems. Part III: Novel 2-alkyl substituents containing cationic heteroaromatics linked via a C-N bond.
abstract: The synthesis and biological activity of a novel series of 2-alkyl-4-pyrrolidinylthio-beta-methylcarbapenems containing a variety of cationic heteroaromatic substituents is described. As a result of these studies, we uncovered a relationship between in vitro antibacterial activity and the length of the alkyl spacer part, and discovered FR20950 (1c), containing a two methylene spacer moiety and an imidazolio group, which possesses a balanced spectrum of antibacterial activity, including Pseudomonas aeruginosa and Methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, FR20950 exhibited excellent urinary recovery, and comparable stability against renal dehydropeptidase-I (DHP-I) to Biapenem. DHP-I stability could be improved by introduction of a substituent on to the imidazole ring.
authors.affiliation: Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan. hidenori_azami@po.fujisawa.co.jp
authors.forename: H
authors.initials: H
authors.lastname: Azami
authors.forename: D
authors.initials: D
authors.lastname: Barrett
authors.forename: K
authors.initials: K
authors.lastname: Matsuda
authors.forename: H
authors.initials: H
authors.lastname: Tsutsumi
authors.forename: K
authors.initials: K
authors.lastname: Washizuka
authors.forename: M
authors.initials: M
authors.lastname: Sakurai
authors.forename: S
authors.initials: S
authors.lastname: Kuroda
authors.forename: F
authors.initials: F
authors.lastname: Shirai
authors.forename: T
authors.initials: T
authors.lastname: Chiba
authors.forename: T
authors.initials: T
authors.lastname: Kamimura
authors.forename: M
authors.initials: M
authors.lastname: Murata
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015780:Carbapenems / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D016106:Methicillin Resistance; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011759:Pyrrolidines / Q000737:chemistry; D051381:Rats; D013057:Spectrum Analysis; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D011759:Pyrrolidines