Discovery of 3‑({5-Chloro-1-[3-(methylsulfonyl)propyl]‑1H‑indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro‑2H‑imidazo[4,5‑c]­pyridin-2-one (JNJ-53718678), a Potent and Orally Bioavailable Fusion Inhibitor of Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) is a seasonal virus that infects the lungs and airways of 64 million children and adults every year. It is a major cause of acute lower respiratory tract infection and is associated with significant morbidity and mortality. Despite the large medical and economic burden, treatment options for RSV-associated bronchiolitis and pneumonia are limited and mainly consist of supportive care. This publication covers the medicinal chemistry efforts resulting in the identification of JNJ-53718678, an orally bioavailable RSV inhibitor that was shown to be efficacious in a phase 2a challenge study in healthy adult subjects and that is currently being evaluated in hospitalized infants and adults. Cocrystal structures of several new derivatives helped in rationalizing some of the structure–activity relationship (SAR) trends observed.

呼吸道合胞病毒（Respiratory syncytial virus, RSV）是一种季节性病毒，每年可感染6400万名儿童与成人的肺部及气道。该病毒是引发急性下呼吸道感染的主要病原体，且与较高的发病率和死亡率密切相关。尽管其带来了沉重的医疗与经济负担，但针对RSV相关细支气管炎及肺炎的治疗选择仍十分有限，且主要以支持治疗为主。本研究涵盖了为发现JNJ-53718678所开展的药物化学研究工作：JNJ-53718678是一种口服生物可利用的RSV抑制剂，在针对健康成年受试者的2a期攻毒试验中被证实具有有效性，目前正于住院婴幼儿及成人群体中开展临床试验评估。数种新型衍生物的共晶结构，有助于阐释本次研究中观察到的部分构效关系（structure–activity relationship, SAR）规律。