Blizzard Timothy A, Chen Helen, Kim Seongkon, Wu Jane, Bodner Rena, Gude Candido, Imbriglio Jason, Young Katherine, Park Young-Whan, Ogawa Aimie, Raghoobar Susan, Hairston Nichelle, Painter Ronald E, Wisniewski Doug, Scapin Giovanna, Fitzgerald Paula, Sharma Nandini, Lu Jun, Ha Sookhee, Hermes Jeff, Hammond Milton L
Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA.
Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA.
Bioorg Med Chem Lett. 2014 Feb 1;24(3):780-5. doi: 10.1016/j.bmcl.2013.12.101. Epub 2014 Jan 3.
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.
制备了具有双环脲核心和各种杂环侧链的β-内酰胺酶抑制剂，并评估其作为与亚胺培南联合使用的潜在伙伴，以克服A类和C类β-内酰胺酶介导的抗生素耐药性。哌啶类似物3（MK-7655）在体外抑制A类和C类β-内酰胺酶。在临床可达到的浓度下，它有效地恢复了亚胺培南对耐亚胺培南的假单胞菌和克雷伯菌菌株的活性。MK-7655和普立万星®的组合目前正处于治疗革兰氏阴性细菌感染的II期临床试验阶段。
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