Qpex Biopharma, Inc., 6275 Nancy Ridge Drive, Suite 100, San Diego, California 92121, United States.
Molsoft LLC, 11199 Sorrento Valley Road, San Diego, California 92121, United States.
J Med Chem. 2020 Jul 23;63(14):7491-7507. doi: 10.1021/acs.jmedchem.9b01976. Epub 2020 Apr 2.
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 . 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 (). 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 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.
尽管在β-内酰胺酶抑制剂领域取得了重大进展，但某些酶仍然对最近引入的抑制剂具有抗性。其中最重要的是肠杆菌科的 B 类（金属）酶 NDM-1 和 OXA 类（D 类）酶。在导致 vaborbactam 的硼酸方案的基础上，努力扩展了该方案的范围，以允许治疗更广泛的生物体。通过对二环先导化合物的关键结构修饰，逐步实现了抑制谱的扩展，最终得到了 QPX7728（）。该化合物显示出非常广泛的抑制谱，包括 B 类和 D 类酶，并且受孔蛋白修饰和外排的影响很小。化合物 是一种有前途的药物，可与β-内酰胺抗生素联合用于治疗广泛的多药耐药革兰氏阴性细菌感染，无论是通过静脉内还是口服给药。
