Oral administration of the pimelic diphenylamide HDAC inhibitor HDACi 4b is unsuitable for chronic inhibition of HDAC activity in the CNS in vivo.
Oral administration of the pimelic diphenylamide HDAC inhibitor HDACi 4b is unsuitable for chronic inhibition of HDAC activity in the CNS in vivo.
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DOI：
10.1371/journal.pone.0044498
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Beaumont V
中科院分区：
文献类型：
--
作者：
Beconi M;Aziz O;Matthews K;Moumné L;O'Connell C;Yates D;Clifton S;Pett H;Vann J;Crowley L;Haughan AF;Smith DL;Woodman B;Bates GP;Brookfield F;Bürli RW;McAllister G;Dominguez C;Munoz-Sanjuan I;Beaumont V
组蛋白脱乙酰酶（HDAC）抑制剂作为多种癌症和神经障碍的潜在治疗剂已经受到相当大的关注。最近发表的关于一类庚二酰二苯酰胺HDAC抑制剂的文章强调了它们在治疗神经退行性疾病弗里德赖希共济失调和亨廷顿病中的前景，其基于在细胞和小鼠模型中的功效。这些研究的作者提出，与基于异羟肟酸的HDAC抑制剂相比，这些化合物的独特作用是由于它们不寻常的慢开/慢关结合动力学，优先与HDAC 3结合，导致独特的药理学特征和降低的毒性。在这里，我们评估了HDAC亚型选择性，细胞活性，吸收，分布，代谢和排泄（ADME）特性，以及一种这样的化合物，HDACi 4 b，先前描述的显示在体内亨廷顿病的R6/2小鼠模型中的功效的中心药效学特征。基于我们在此报道的数据，我们得出结论，虽然体外选择性和结合模式在很大程度上与以前的报道一致，但HDACi 4 b的理化性质、代谢和P-糖蛋白（Pgp）底物倾向使该化合物在研究小鼠口服给药的体内中心I类HDAC抑制方面次优。在先前的概念验证研究中使用了使用溶解在饮用水中的HDACi 4 b的药物施用方案，对CNS HDAC 3抑制作为治疗亨廷顿病的靶标的验证产生了怀疑。我们强调的物理化学稳定性和代谢问题与4 b可能是内在的负债的苯甲酰胺化学型一般。
Histone deacetylase (HDAC) inhibitors have received considerable attention as potential therapeutics for a variety of cancers and neurological disorders. Recent publications on a class of pimelic diphenylamide HDAC inhibitors have highlighted their promise in the treatment of the neurodegenerative diseases Friedreich’s ataxia and Huntington’s disease, based on efficacy in cell and mouse models. These studies’ authors have proposed that the unique action of these compounds compared to hydroxamic acid-based HDAC inhibitors results from their unusual slow-on/slow-off kinetics of binding, preferentially to HDAC3, resulting in a distinctive pharmacological profile and reduced toxicity. Here, we evaluate the HDAC subtype selectivity, cellular activity, absorption, distribution, metabolism and excretion (ADME) properties, as well as the central pharmacodynamic profile of one such compound, HDACi 4b, previously described to show efficacy in vivo in the R6/2 mouse model of Huntington’s disease. Based on our data reported here, we conclude that while the in vitro selectivity and binding mode are largely in agreement with previous reports, the physicochemical properties, metabolic and p-glycoprotein (Pgp) substrate liability of HDACi 4b render this compound suboptimal to investigate central Class I HDAC inhibition in vivo in mouse per oral administration. A drug administration regimen using HDACi 4b dissolved in drinking water was used in the previous proof of concept study, casting doubt on the validation of CNS HDAC3 inhibition as a target for the treatment of Huntington’s disease. We highlight physicochemical stability and metabolic issues with 4b that are likely intrinsic liabilities of the benzamide chemotype in general.
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