title: SYN-1012: a new beta-lactamase inhibitor of penem skeleton.
abstract: A new beta-lactamase inhibitor, SYN-1012, with a penem skeleton was synthesized and its biological activity compared with clavulanic acid, sulbactam, tazobactam and BRL-42715. The beta-lactamase inhibitory activity of SYN-1012 was comparable to BRL-42715. Clavulanate and penam sulphones (sulbactam and tazobactam) were more active against TEM-1 and OXA-1, but were less active against TEM-3 and cephalosporinase (Case) than SYN-1012. In combination with piperacillin, SYN-1012 exhibited comparable or slightly lower synergistic effects than BRL-42715 against all the Gram-positive and Gram-negative isolates tested with only exception of Pseudomonas aeruginosa. The separate combinations of SYN-1012 and BRL-42715 with ceftazidime and cefotaxime provided comparable results against Gram-negatives, but not against Gram-positive isolates. Tazobactam was inferior to SYN-1012 in all cases. In comparison to tazobactam, SYN-1012 and BRL-42715 were relatively unstable in human and mouse plasma, and in mouse liver and kidney homogenates. Serum level of SYN-1012 and BRL-42715 after an intravenous administration of 20 mg/kg in rabbit was undetectable after 1 hour.
authors.affiliation: SynPhar Laboratories Inc., Taiho Alberta Center, Canada.
authors.forename: O A
authors.initials: OA
authors.lastname: Phillips
authors.forename: D P
authors.initials: DP
authors.lastname: Czajkowski
authors.forename: P
authors.initials: P
authors.lastname: Spevak
authors.forename: M P
authors.initials: MP
authors.lastname: Singh
authors.forename: C
authors.initials: C
authors.lastname: Hanehara-Kunugita
authors.forename: A
authors.initials: A
authors.lastname: Hyodo
authors.forename: R G
authors.initials: RG
authors.lastname: Micetich
authors.forename: S N
authors.initials: SN
authors.lastname: Maiti
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007769:Lactams; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D011817:Rabbits; D000078142:Tazobactam; D047090:beta-Lactams
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007769:Lactams; C106756:SYN 1012; D047090:beta-Lactams; C061593:C6-(N1-methyl-1,2,3-trazolylmethylene)penem; D010397:Penicillanic Acid; D000078142:Tazobactam