title: Synthesis and biological activity of AM-112 and related oxapenem analogues.
abstract: Thirty five oxapenem analogues substituted with a range of tertiary groups at C-2 have been synthesised and evaluated as broad-spectrum beta-lactamase inhibitors. All analogues enhanced the activity of ceftazidime against bacterial isolates producing Class A and Class C beta-lactamases. Compounds with cyclic substituents at C-1' (attached to C-6) were associated with enhanced antibacterial activity against Staphylococcus aureus. (R) Stereochemistry at C-1' led to synergistic activity against beta-lactamase negative enterococci. (S) Stereochemistry at C-1' was associated with enhanced inhibition of Class A beta-lactamases and lack of synergistic activity against enterococci. AM-113 was unstable in serum and not detectable following subcutaneous or oral dosing in mice. AM-112 and AM-115 achieved good serum levels following subcutaneous dosing. AM-114 exhibited 30% bioavailability following oral dosing. AM-112 [(1'R,5R,6R)-2-(4-ammonio-1,1-dimethylbutyl)-6-(1'-hydroxyethyl)oxapenem-3-carboxylate] achieved the greatest protection of ceftazidime against Gram-negatives producing Class A or C beta-lactamases.
authors.affiliation: Micron Research Ltd., ELY, CB7 4JY, UK. iain.simpson@micron-research.com
authors.forename: Iain N
authors.initials: IN
authors.lastname: Simpson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Urch
authors.forename: Gudrun
authors.initials: G
authors.lastname: Hagen
authors.forename: Ralf
authors.initials: R
authors.lastname: Albrecht
authors.forename: Birgit
authors.initials: B
authors.lastname: Sprinkart
authors.forename: Hans R
authors.initials: HR
authors.lastname: Pfaendler
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002442:Ceftazidime / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D007769:Lactams; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D051381:Rats; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C476288:(1'R,5R,6R)-3-(4-amino-1,1-dimethyl-butyl)-6-(1'-hydroxyethyl)oxapenem-3-carboxylate; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007769:Lactams; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D002442:Ceftazidime