Optimization of LpxC Inhibitor Lead Compounds Focusing on Efficacy and Formulation for High Dose Intravenous Administration.,Journal of Medicinal Chemistry

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Optimization of LpxC Inhibitor Lead Compounds Focusing on Efficacy and Formulation for High Dose Intravenous Administration.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-12-23 , DOI: 10.1021/acs.jmedchem.9b01605
Philippe Panchaud ₁ , Jean-Philippe Surivet ₁ , Stefan Diethelm ₁ , Anne-Catherine Blumstein ₁ , Jean-Christophe Gauvin ₁ , Loïc Jacob ₁ , Florence Masse ₁ , Gaëlle Mathieu ₁ , Azely Mirre ₁ , Christine Schmitt ₁ , Michel Enderlin-Paput ₁ , Roland Lange ₁ , Carmela Gnerre ₁ , Swen Seeland ₁ , Charlyse Herrmann ₁ , Hans H Locher ₁ , Peter Seiler ₁ , Daniel Ritz ₁ , Georg Rueedi ₁

Affiliation

LpxC inhibitors were optimized starting from lead compounds with limited efficacy and solubility and with the goal to provide new options for the treatment of serious infections caused by Gram-negative pathogens in hospital settings. To enable the development of an aqueous formulation for intravenous administration of the drug at high dose, improvements in both solubility and antibacterial activity in vivo were prioritized early on. This lead optimization program resulted in the discovery of compounds such as 13 and 30, which exhibited high solubility and potent efficacy against Gram-negative pathogens in animal infection models.

中文翻译：

LpxC抑制剂前导化合物的优化，着重于高剂量静脉给药的功效和配方。

LpxC抑制剂从具有有限功效和溶解度的先导化合物开始进行了优化，目的是为医院环境中革兰氏阴性病原体引起的严重感染的治疗提供新的选择。为了能够开发用于高剂量静脉内给药的水性制剂，早期就优先考虑了体内溶解性和抗菌活性的改善。该前导优化程序导致发现诸如13和30的化合物，它们在动物感染模型中显示出高溶解性和针对革兰氏阴性病原体的有效功效。

更新日期：2019-12-23

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