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Discovery of Cyclic Boronic Acid QPX7728, an Ultrabroad-Spectrum Inhibitor of Serine and Metallo-β-lactamases.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-03-09 , DOI: 10.1021/acs.jmedchem.9b01976 Scott J Hecker 1 , K Raja Reddy 1 , Olga Lomovskaya 1 , David C Griffith 1 , Debora Rubio-Aparicio 1 , Kirk Nelson 1 , Ruslan Tsivkovski 1 , Dongxu Sun 1 , Mojgan Sabet 1 , Ziad Tarazi 1 , Jonathan Parkinson 1 , Maxim Totrov 2 , Serge H Boyer 1 , Tomasz W Glinka 1 , Orville A Pemberton 3 , Yu Chen 3 , Michael N Dudley 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-03-09 , DOI: 10.1021/acs.jmedchem.9b01976 Scott J Hecker 1 , K Raja Reddy 1 , Olga Lomovskaya 1 , David C Griffith 1 , Debora Rubio-Aparicio 1 , Kirk Nelson 1 , Ruslan Tsivkovski 1 , Dongxu Sun 1 , Mojgan Sabet 1 , Ziad Tarazi 1 , Jonathan Parkinson 1 , Maxim Totrov 2 , Serge H Boyer 1 , Tomasz W Glinka 1 , Orville A Pemberton 3 , Yu Chen 3 , Michael N Dudley 1
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Despite major advances in the β-lactamase inhibitor field, certain enzymes remain refractory to inhibition by agents recently introduced. Most important among these are the class B (metallo) enzyme NDM-1 of Enterobacteriaceae and the class D (OXA) enzymes of Acinetobacter baumannii. Continuing the boronic acid program that led to vaborbactam, efforts were directed toward expanding the spectrum to allow treatment of a wider range of organisms. Through key structural modifications of a bicyclic lead, stepwise gains in spectrum of inhibition were achieved, ultimately resulting in QPX7728 (35). This compound displays a remarkably broad spectrum of inhibition, including class B and class D enzymes, and is little affected by porin modifications and efflux. Compound 35 is a promising agent for use in combination with a β-lactam antibiotic for the treatment of a wide range of multidrug resistant Gram-negative bacterial infections, by both intravenous and oral administration.
中文翻译：
发现环硼酸QPX7728，一种丝氨酸和金属β-内酰胺酶的超广谱抑制剂。
尽管β-内酰胺酶抑制剂领域取得了重大进展，但某些酶仍对最近引入的药物的抑制作用具有抵抗力。其中最重要的是肠杆菌科的B类（金属）酶NDM-1和鲍曼不动杆菌的D类（OXA）酶。继续实施导致vaborbactam的硼酸计划，努力扩大光谱范围，以治疗更广泛的生物。通过双环先导的关键结构修饰，抑制谱逐步提高，最终得到QPX7728（35）。该化合物显示出极大的抑制谱，包括B类和D类酶，几乎不受孔蛋白修饰和外排的影响。化合物35 是与β-内酰胺类抗生素组合使用的有前途的药物，可通过静脉内和口服给药治疗多种多重耐药性革兰氏阴性细菌感染。
更新日期：2020-03-09
中文翻译：
发现环硼酸QPX7728，一种丝氨酸和金属β-内酰胺酶的超广谱抑制剂。
尽管β-内酰胺酶抑制剂领域取得了重大进展，但某些酶仍对最近引入的药物的抑制作用具有抵抗力。其中最重要的是肠杆菌科的B类（金属）酶NDM-1和鲍曼不动杆菌的D类（OXA）酶。继续实施导致vaborbactam的硼酸计划，努力扩大光谱范围，以治疗更广泛的生物。通过双环先导的关键结构修饰，抑制谱逐步提高，最终得到QPX7728（35）。该化合物显示出极大的抑制谱，包括B类和D类酶，几乎不受孔蛋白修饰和外排的影响。化合物35 是与β-内酰胺类抗生素组合使用的有前途的药物，可通过静脉内和口服给药治疗多种多重耐药性革兰氏阴性细菌感染。
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