Side chain SAR of bicyclic β-lactamase inhibitors (BLIs). 1. Discovery of a class C BLI for combination with imipinem

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 3, 2010, Pages 918-921

  Blizzard, Timothy A ^a   Chen, Helen ^a   Kim, Seongkon ^a   Wu, Jane ^a   Young, Katherine ^a   Park, Young Whan ^a   Ogawa, Amy ^a   Raghoobar, Susan ^a   Painter, Ronald E ^a   Hairston, Nichelle ^a   Lee, Sang Ho ^a   Misura, Andrew ^a   Felcetto, Tom ^a   Fitzgerald, Paula ^a   Sharma, Nandini ^a   Lu, Jun ^a   Ha, Sookhee ^a   Hickey, Emily ^a   Hermes, Jeff ^a   Hammond, Milton L ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Carbapenem; Imipenem; Inhibitor; Lactamase

Indexed keywords

AZEPINE DERIVATIVE; BETA LACTAMASE INHIBITOR; CILASTATIN PLUS IMIPENEM; IMIPENEM; MONOBACTAM DERIVATIVE; PIPERIDINE DERIVATIVE; BETA LACTAMASE; CARBAPENEM DERIVATIVE; DRUG COMBINATION; FUSED HETEROCYCLIC RINGS;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIBIOTIC RESISTANCE; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG IDENTIFICATION; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; PSEUDOMONAS AERUGINOSA; SPLEEN; STRUCTURE ACTIVITY RELATION; ANIMAL; CHEMISTRY; COMPARATIVE STUDY; DRUG COMBINATION; DRUG DEVELOPMENT; DRUG EFFECTS; ENZYMOLOGY; METABOLISM; PHYSIOLOGY; PROCEDURES; PSEUDOMONAS INFECTIONS;

ANIMALS; BETA-LACTAM RESISTANCE; BETA-LACTAMASE INHIBITORS; BETA-LACTAMASES; BICYCLO COMPOUNDS, HETEROCYCLIC; CARBAPENEMS; DRUG COMBINATIONS; DRUG DISCOVERY; IMIPENEM; MICE; PSEUDOMONAS AERUGINOSA; PSEUDOMONAS INFECTIONS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 74049135431     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.12.069     Document Type: Article

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21. Azepinone 15 was purchased from Tyger Scientific (www.tygersci.com).
22. An improved synthesis of 18 was developed by Merck Process Research and will be published separately.
23. X-ray coordinates for 2 (PDB code 2wzx) and 3 (2wzz) have been deposited in the RCSB Protein Data Bank (PDB) database.
24. 50 was determined from semi-logarithmic plots of enzyme inhibition versus inhibitor concentration; (c) In vitro synergy assay: The assay determines the concentration of BLI required to reduce the MIC of imipenem by one-half, one-quarter, one-eighth, one-sixteenth and one-thirty-second against resistant bacteria. The BLI was titrated in a serial dilution across a microtiter plate while at the same time imipenem was titrated in a serial dilution down the microtiter plate. The plate was inoculated with the bacterial strain in question then incubated overnight and evaluated for bacterial growth. Each well in the microplate checkerboard contains a different combination of concentrations of the inhibitor and the antibiotic thus allowing determination of synergy between the two.
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26. Lactam 24a is commercially available (Matrix). Lactams 24b and 24c were prepared by condensation of N,N′-bis-benzyl ethylene diamine and N-benzyl-N-BOC-ethanolamine, respectively, with the methyl ester of N-CBZ-2-aziridine carboxylic acid followed by cyclization of the intermediate amino ester to afford the desired lactam.
27. Young, K. et al., in preparation.
28. Lee, S. et al., in preparation.