Kati Warren M, Montgomery Debra, Carrick Robert, Gubareva Larisa, Maring Clarence, McDaniel Keith, Steffy Kevin, Molla Akhteruzzaman, Hayden Frederick, Kempf Dale, Kohlbrenner William
Antiviral Drug Discovery Research, Abbott Laboratories, Abbott Park, Illinois 60064-6217, USA.
Antimicrob Agents Chemother. 2002 Apr;46(4):1014-21. doi: 10.1128/AAC.46.4.1014-1021.2002.
A-315675 is a novel, pyrrolidine-based compound that was evaluated in this study for its ability to inhibit A and B strain influenza virus neuraminidases in enzyme assays and influenza virus replication in cell culture. A-315675 effectively inhibited influenza A N1, N2, and N9 and B strain neuraminidases with inhibitor constant (K(i)) values between 0.024 and 0.31 nM. These values were comparable to or lower than the K(i) values measured for oseltamivir carboxylate (GS4071), zanamivir, and BCX-1812, except for the N1 enzymes that were found to be the most sensitive to BCX-1812. The time-dependent inhibition of neuraminidase catalytic activity observed with A-315675 is likely due to its very low rate of dissociation from the active site of neuraminidase. The half times for dissociation of A-315675 from B/Memphis/3/89 and A/Tokyo/3/67 (H3N2) influenza virus neuraminidases of 10 to 12 h are significantly slower than the half times measured for oseltamivir carboxylate (33 to 60 min). A-315675 inhibited the replication of several laboratory strains of influenza virus in cell culture with potencies that were comparable or superior to those for oseltamivir carboxylate and BCX-1812, except for the A/H1N1 viruses that were found to be two- to fourfold more susceptible to BCX-1812. A-315675 and oseltamivir carboxylate exhibited comparable potencies against a panel of A/H1N1 and A/H3N2 influenza virus clinical isolates, but A-315675 was found to be significantly more potent than oseltamivir carboxylate against the B strain isolates. The favorable in vitro results relative to other clinically effective agents provide strong support for the further investigation of A-315675 as a potential therapy for influenza virus infections.
A-315675是一种新型的基于吡咯烷的化合物，本研究评估了其在酶分析中抑制甲型和乙型流感病毒神经氨酸酶的能力以及在细胞培养中抑制流感病毒复制的能力。A-315675能有效抑制甲型流感病毒N1、N2和N9以及乙型流感病毒神经氨酸酶，其抑制常数（K(i)）值在0.024至0.31 nM之间。这些值与羧基奥司他韦（GS4071）、扎那米韦和BCX-1812测得的K(i)值相当或更低，但发现N1酶对BCX-1812最为敏感。观察到A-315675对神经氨酸酶催化活性的时间依赖性抑制可能是由于其从神经氨酸酶活性位点解离的速率非常低。A-315675从B/孟菲斯/3/89和A/东京/3/67（H3N2）流感病毒神经氨酸酶解离的半衰期为10至12小时，明显慢于羧基奥司他韦测得的半衰期（33至60分钟）。A-315675在细胞培养中抑制了几种实验室流感病毒株的复制，其效力与羧基奥司他韦和BCX-1812相当或更高，但发现A/H1N1病毒对BCX-1812的敏感性高两至四倍。A-315675和羧基奥司他韦对一组甲型H1N1和甲型H3N2流感病毒临床分离株表现出相当的效力，但发现A-315675对乙型流感病毒分离株的效力明显高于羧基奥司他韦。相对于其他临床有效药物而言，这些有利的体外研究结果为进一步研究A-315675作为流感病毒感染的潜在治疗方法提供了有力支持。
