title: Discovery of MK-7655, a β-lactamase inhibitor for combination with Primaxin®.
abstract: β-Lactamase inhibitors with a bicyclic urea core and a variety of heterocyclic side chains were prepared and evaluated as potential partners for combination with imipenem to overcome class A and C β-lactamase mediated antibiotic resistance. The piperidine analog 3 (MK-7655) inhibited both class A and C β-lactamases in vitro. It effectively restored imipenem's activity against imipenem-resistant Pseudomonas and Klebsiella strains at clinically achievable concentrations. A combination of MK-7655 and Primaxin® is currently in phase II clinical trials for the treatment of Gram-negative bacterial infections.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA. Electronic address: timblizzard@comcast.net.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Blizzard
authors.affiliation: Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Seongkon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Rena
authors.initials: R
authors.lastname: Bodner
authors.affiliation: Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Candido
authors.initials: C
authors.lastname: Gude
authors.affiliation: Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Imbriglio
authors.affiliation: Department of Infectious Diseases, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Young
authors.affiliation: Department of Infectious Diseases, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Young-Whan
authors.initials: YW
authors.lastname: Park
authors.affiliation: Department of Infectious Diseases, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Aimie
authors.initials: A
authors.lastname: Ogawa
authors.affiliation: Department of Infectious Diseases, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Raghoobar
authors.affiliation: Department of Infectious Diseases, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Nichelle
authors.initials: N
authors.lastname: Hairston
authors.affiliation: Department of Infectious Diseases, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Painter
authors.affiliation: Department of Infectious Diseases, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Doug
authors.initials: D
authors.lastname: Wisniewski
authors.affiliation: Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scapin
authors.affiliation: Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Fitzgerald
authors.affiliation: Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Nandini
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Sookhee
authors.initials: S
authors.lastname: Ha
authors.affiliation: Department of Infectious Diseases, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Hermes
authors.affiliation: Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA; Department of Infectious Diseases, Merck Research Labs, Rahway, NJ 07065, USA.
authors.forename: Milton L
authors.initials: ML
authors.lastname: Hammond
mesh_terms: D053961:Azabicyclo Compounds / Q000737:chemistry* / Q000494:pharmacology*; D015377:Cilastatin / Q000737:chemistry* / Q000494:pharmacology; D000077728:Cilastatin, Imipenem Drug Combination; D018360:Crystallography, X-Ray; D004338:Drug Combinations; D055808:Drug Discovery; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry*; D015378:Imipenem / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007709:Klebsiella / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011549:Pseudomonas / Q000187:drug effects; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors
chemical_list: D053961:Azabicyclo Compounds; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D015377:Cilastatin; D015378:Imipenem; D000077728:Cilastatin, Imipenem Drug Combination; C568736:relebactam
keywords: Antibacterial; Antibiotic; Imipenem; MK-7655; β-Lactamase inhibitor