ACS medicinal chemistry letters · 2024
Invention of VH-937, a Potent HIV-1 Maturation Inhibitor with the Potential for Infrequent Oral Dosing in Humans.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Sit Sing-Yuen, Chen Yan, Chen Jie, Venables Brian L, Swidorski Jacob J, Xu Li, Sin Ny, Hartz Richard A, Lin Zeyu, Zhang Sharon, Li Zhufang, Wu Dauh-Rurng, Li Peng, Kempson James, Hou Xiaoping, Shanmugam Yoganand, Parker Dawn, Jenkins Susan, Simmermacher Jean, Falk Paul, McAuliffe Brian, Cockett Mark, Hanumegowda Umesh, Dicker Ira, Krystal Mark, Meanwell Nicholas A, Regueiro-Ren Alicia
Аннотация
Newer generation HIV-1 maturation inhibitors have proven to be viable antiretroviral agents in the clinic. VH3739937, (VH-937, 24) is an advanced HIV-1 maturation inhibitor (MI) with a 4-cyanopyridyl ether replacing the fluorine present in the previous lead MI GSK3640254 (GSK254, 3). The introduction of aromatic methylene ethers α to the carboxylic acid moiety significantly enhanced the antiviral profile, with additional inhibitory effects observed toward the A364V mutation, the primary resistance mutation emerging in response to selective pressure by MIs. Structure-activity optimization led to the invention of VH-937, which combined the best overall antiviral profile with pharmacokinetic properties in animal models. These properties indicate the potential for infrequent dosing, a finding confirmed in initial clinical studies in humans that suggests its potential as a once-weekly dosing agent.