Murphy-Benenato Kerry E, Bhagunde Pratik R, Chen April, Davis Hajnalka E, Durand-Réville Thomas F, Ehmann David E, Galullo Vincent, Harris Jennifer J, Hatoum-Mokdad Holia, Jahić Haris, Kim Aryun, Manjunatha M R, Manyak Erika L, Mueller John, Patey Sara, Quiroga Olga, Rooney Michael, Sha Li, Shapiro Adam B, Sylvester Mark, Tan Beesan, Tsai Andy S, Uria-Nickelsen Maria, Wu Ye, Zambrowski Mark, Zhao Shannon X
Infection Innovative Medicines and ‡Discovery Sciences, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
J Med Chem. 2015 Mar 12;58(5):2195-205. doi: 10.1021/jm501506f. Epub 2015 Mar 3.
To identify new agents for the treatment of multi-drug-resistant Pseudomonas aeruginosa, we focused on siderophore-conjugated monocarbams. This class of monocyclic β-lactams are stable to metallo-β-lactamases and have excellent P. aeruginosa activities due to their ability to exploit the iron uptake machinery of Gram-negative bacteria. Our medicinal chemistry plan focused on identifying a molecule with optimal potency and physical properties and activity for in vivo efficacy. Modifications to the monocarbam linker, siderophore, and oxime portion of the molecules were examined. Through these efforts, a series of pyrrolidinone-based monocarbams with good P. aeruginosa cellular activity (P. aeruginosa MIC90 = 2 μg/mL), free fraction levels (>20% free), and hydrolytic stability (t1/2 ≥ 100 h) were identified. To differentiate the lead compounds and enable prioritization for in vivo studies, we applied a semi-mechanistic pharmacokinetic/pharmacodynamic model to enable prediction of in vivo efficacy from in vitro data.
为了鉴定用于治疗多重耐药铜绿假单胞菌的新型药物，我们将重点放在了铁载体共轭单碳青霉烯类药物上。这类单环β-内酰胺类药物对金属β-内酰胺酶稳定，并且由于能够利用革兰氏阴性菌的铁摄取机制而对铜绿假单胞菌具有优异的活性。我们的药物化学计划着重于鉴定一种具有最佳效力、物理性质以及体内疗效活性的分子。对分子的单碳青霉烯连接子、铁载体和肟部分进行了修饰研究。通过这些努力，鉴定出了一系列基于吡咯烷酮的单碳青霉烯类药物，它们对铜绿假单胞菌具有良好的细胞活性（铜绿假单胞菌MIC90 = 2 μg/mL）、游离分数水平（>20%游离）以及水解稳定性（t1/2≥100小时）。为了区分先导化合物并确定体内研究的优先级，我们应用了一种半机制药代动力学/药效学模型，以便能够根据体外数据预测体内疗效。
