Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety
Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety
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DOI：
10.1002/cmdc.201900287
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发表时间：
2019-08-05
期刊：
影响因子：
3.4
通讯作者：
Cirz, Ryan T.
中科院分区：
文献类型：
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作者：
Cohen, Frederick;Aggen, James B.;Cirz, Ryan T.
UDP-3-O-（r -3-羟基肉豆蔻酰基）- n -乙酰氨基葡萄糖脱乙酰酶（LpxC）是一种Zn2+脱乙酰酶，对大多数致病性革兰氏阴性菌的生存至关重要。ACHN-975 （N-（S)-3-氨基-1-（羟氨基）-3-甲基-1-氧丁酮-2-基）-4-（（1R,2R)-2-（羟甲基）环丙基）丁-1,3-二因-1-基）苯酰胺）是第一个达到人体临床试验的LpxC抑制剂，被发现具有剂量限制的心血管毒性，可引起短暂性低血压，无代偿性心动过速。在此，我们报告了在ACHN-975之外发现LpxC抑制剂的努力，这些抑制剂在酶效、抗菌活性、药代动力学和心血管安全性方面进行了优化。基于其整体结构特征，选择化合物26 (LPXC-516, （S)- n-（2-（羟氨基）-1-（3-甲氧基-1,1-二氧化乙烷-3-基）-2-氧乙基）-4-（6-羟基己-1,3-二炔-1-基）苯酰胺）进行进一步开发。开发了一种磷酸26前药，其溶解度为bbb30 mg mL(-1)，可用于肠外给药，并在约2分钟的t（1/2）内转化为活性药物。出乎意料的是，尽管我们的优化努力，26的前药仍然有一个治疗窗口不足以支持进一步的临床开发。
UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL(-1) for parenteral administration and conversion into the active drug with a t(1/2) of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.