Oral Administration of the Pimelic Diphenylamide HDAC Inhibitor HDACi 4b Is Unsuitable for Chronic Inhibition of HDAC Activity in the CNS In Vivo

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.

组蛋白去乙酰化酶（HDAC）抑制剂作为多种癌症与神经系统疾病的潜在治疗手段，已受到广泛关注。近年来，针对庚二酰二苯酰胺类HDAC抑制剂的多项研究显示，基于细胞与小鼠模型中的疗效，这类化合物在治疗神经退行性疾病弗里德赖希共济失调与亨廷顿病方面颇具前景。上述研究的作者提出，相较于基于异羟肟酸的HDAC抑制剂，这类化合物的独特作用机制源于其与HDAC3优先结合时表现出的罕见慢结合/慢解离动力学，由此形成了独特的药理学特征并降低了毒性。本研究针对其中一种化合物HDACi 4b展开评估——此前已有研究表明，该化合物在亨廷顿病的R6/2小鼠模型中展现出体内疗效。本次评估涵盖了HDAC亚型选择性、细胞活性、吸收、分布、代谢与排泄（ADME）特性，以及其中枢药效学特征。基于本文报道的实验数据，我们得出结论：尽管体外选择性与结合模式大体与既往研究一致，但HDACi 4b的理化性质、代谢特性以及作为P-糖蛋白（Pgp）底物的倾向性，使得该化合物并不适合通过小鼠口服给药的方式，在体内开展中枢神经系统I类HDAC抑制相关研究。既往概念验证研究采用了将HDACi 4b溶于饮用水的给药方案，这使得“中枢神经系统HDAC3抑制可作为亨廷顿病治疗靶点”这一结论的有效性受到质疑。我们同时指出，化合物4b存在的理化稳定性与代谢问题，大概率是苯甲酰胺类化学型普遍存在的固有缺陷。