Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
J Med Chem. 2015 Feb 26;58(4):1630-43. doi: 10.1021/jm5017768. Epub 2015 Jan 27.
GS-5806 is a novel, orally bioavailable RSV fusion inhibitor discovered following a lead optimization campaign on a screening hit. The oral absorption properties were optimized by converting to the pyrazolo[1,5-a]-pyrimidine heterocycle, while potency, metabolic, and physicochemical properties were optimized by introducing the para-chloro and aminopyrrolidine groups. A mean EC50 = 0.43 nM was found toward a panel of 75 RSV A and B clinical isolates and dose-dependent antiviral efficacy in the cotton rat model of RSV infection. Oral bioavailability in preclinical species ranged from 46 to 100%, with evidence of efficient penetration into lung tissue. In healthy human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a mean 4.2 log10 reduction in peak viral load and a significant reduction in disease severity compared to placebo. In conclusion, a potent, once daily, oral RSV fusion inhibitor with the potential to treat RSV infection in infants and adults is reported.
GS-5806 是一种新型的、口服生物可利用的 RSV 融合抑制剂，是在对筛选出的先导化合物进行优化后发现的。通过将其转化为吡唑并[1,5-a]嘧啶杂环，优化了口服吸收特性，同时通过引入对氯和氨基吡咯烷基团，优化了其效力、代谢和物理化学性质。对 75 株 RSV A 和 B 临床分离株的检测发现，其对 RSV 的 EC50 平均为 0.43 nM，并在 RSV 感染的棉鼠模型中表现出剂量依赖性的抗病毒功效。在临床前物种中的口服生物利用度范围为 46%至 100%，并且有证据表明其能够有效地渗透到肺部组织中。在 RSV 感染的健康人类志愿者中进行的临床试验中，与安慰剂相比，该药物表现出了强大的抗病毒作用，平均可使峰值病毒载量降低 4.2 个对数，并且显著降低了疾病严重程度。总之，报告了一种具有潜力的、每日一次口服的 RSV 融合抑制剂，可用于治疗婴儿和成人的 RSV 感染。
