Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
J Med Chem. 2011 Nov 24;54(22):7834-47. doi: 10.1021/jm2008826. Epub 2011 Oct 27.
Novel non-fluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. Aminopiperidines that have a bicyclic aromatic moiety linked through a carbon to an ethyl bridge, such as 1, generally show potent broad-spectrum antibacterial activity, including quinolone-resistant isolates, but suffer from potent hERG inhibition (IC(50)= 3 μM for 1). We now disclose the finding that new analogues of 1 with an N-linked cyclic amide moiety attached to the ethyl bridge, such as 24m, retain the broad-spectrum antibacterial activity of 1 but show significantly less hERG inhibition (IC(50)= 31 μM for 24m) and higher free fraction than 1. One optimized analogue, compound 24l, showed moderate clearance in the dog and promising efficacy against Staphylococcus aureus in a mouse thigh infection model.
新型非氟喹诺酮类细菌拓扑异构酶 II（DNA 回旋酶和拓扑异构酶 IV）抑制剂是开发新型抗菌药物的研究热点，此类药物不受与氟喹诺酮类药物发生的靶介导交叉耐药性的影响。具有双环芳基部分并通过碳连接到乙基桥的氨基哌啶类化合物，如 1，通常显示出强大的广谱抗菌活性，包括对喹诺酮类耐药的分离株，但具有很强的 hERG 抑制作用（IC50=1 的 3 μM）。我们现在发现，1 的乙基桥连接的 N-连接环酰胺部分的新型类似物，如 24m，保留了 1 的广谱抗菌活性，但 hERG 抑制作用明显减弱（IC50=24m 的 31 μM），游离分数高于 1。一种优化的类似物，化合物 24l，在狗体内清除率适中，并在小鼠大腿感染模型中对金黄色葡萄球菌显示出有希望的疗效。
