Journal of medicinal chemistry · 2021
Discovery of Ethyl Ketone-Based Highly Selective HDACs 1, 2, 3 Inhibitors for HIV Latency Reactivation with Minimum Cellular Potency Serum Shift and Reduced hERG Activity.
СтатьяНазвание и аннотация: Перевод в очереди
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Yu Wensheng, Liu Jian, Clausen Dane, Yu Younong, Duffy Joseph L, Wang Ming, Xu Shouning, Deng Lin, Suzuki Takao, Chung Christine C, Myers Robert W, Klein Daniel J, Fells James I, Holloway M Katharine, Wu Jin, Wu Guoxin, Howell Bonnie J, Barnard Richard J O, Kozlowski Joseph
Аннотация
We describe the discovery of histone deacetylase (HDACs) 1, 2, and 3 inhibitors with ethyl ketone as the zinc-binding group. These HDACs 1, 2, and 3 inhibitors have good enzymatic and cellular activity. Their serum shift in cellular potency has been minimized, and selectivity against hERG has been improved. They are also highly selective over HDACs 6 and 8. These inhibitors contain a variety of substituted heterocycles on the imidazole or oxazole scaffold. Compounds 31 and 48 stand out due to their good potency, high selectivity over HDACs 6 and 8, reduced hERG activity, optimized serum shift in cellular potency, and good rat and dog PK profiles.