title: SM-216601, a novel parenteral 1beta-methylcarbapenem: structure-activity relationships of antibacterial activity and neurotoxicity in mice.
abstract: It has been reported that 2-(4-substituted thiazol-2-ylthio)-1beta-methyl-carbapenems exhibit potent activity against methicillin-resistant staphylococci (MRS) and vancomycin-resistant enterococci (VRE). In order to develop a novel broad-spectrum carbapenem, the structure-activity relationships of a series of 2-(4-tetrahydropyridinylthiazol-2-ylthio)-1beta-methylcarbapenems and 4-dihydropyrrolyl thiazole analogs were investigated with regard to their activity against Gram-positive and especially Gram-negative bacteria and also their convulsant activity, which is a major side effect concern of carbapenems. The introduction of substituent(s) on the dihydropyrrole moiety did not cause remarkable changes in anti-MRS and VRE activities, but tended to lower the anti-Gram-negative bacterial activity except in some cases of methyl group introduction. These substitutions did however cause a reduction of the convulsant activity, which was affected by the size and also the configuration of the substituent. In the case of SM-216601 (6), introduction of a methyl group brought about significant reduction in neurotoxicity while maintaining favorable anti-Gram-negative bacterial activity.
authors.affiliation: Sumitomo Pharmaceuticals Research Division, 1-98, Kasugade Naka 3-Chome, Konohana-ku, Osaka 554-0022, Japan,
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ueda
authors.forename: Masanori
authors.initials: M
authors.lastname: Itoh
authors.forename: Akira
authors.initials: A
authors.lastname: Sasaki
authors.forename: Makoto
authors.initials: M
authors.lastname: Sunagawa
mesh_terms: D000818:Animals; D001419:Bacteria / Q000187:drug effects*; D015780:Carbapenems / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D003292:Convulsants / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D012640:Seizures / Q000139:chemically induced; D013055:Spectrophotometry, Infrared; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship
chemical_list: D015780:Carbapenems; D003292:Convulsants; C500116:SM-216601