A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC1 enzyme and COLO 205 cellular IC₅₀), liver microsomal stability (t_1/2), cytochrome P450 inhibitory (3A4 IC₅₀), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dose-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.

中文翻译：

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发现（2 E）-3- {2-丁基-1- [2-（二乙基氨基）乙基] -1 H-苯并咪唑-5-基} -N-羟基丙烯酰胺（SB939），一种口服活性组蛋白脱乙酰基酶抑制剂优越的临床前资料

设计并合成了一系列3-（1,2-二取代-1 H-苯并咪唑-5-基）-N-羟基丙烯酰胺（1）作为HDAC抑制剂。已经建立了广泛的SAR，用于体外效价（HDAC1酶和COLO 205细胞IC ₅₀），肝微粒体稳定性（t _1/2），细胞色素P450抑制（3A4 IC ₅₀）和clogP等。通过仔细调节苯并咪唑环的1和2位的取代基可以对这些参数进行微调。在对所选化合物进行全面的体外和体内分析后，SB939（3）被确定为临床前开发候选药物。3是一种有效的泛HDAC抑制剂，具有出色的类药物特性，在体内肿瘤模型（HCT-116，PC-3，A2780，MV4-11，Ramos）中非常有效，并且具有高剂量比例口服暴露，非常好ADME，安全性和药物特性。当口服给药给荷瘤小鼠时，3富含肿瘤组织，这可能有助于其有效的抗肿瘤活性和延长作用时间。3目前正在相I和II期临床试验中测试。