Abstract：
Monoamine oxidases (MAOA/MAOB) are enzymes known for their role in neurotransmitter regulation in the central nervous system (CNS). Irreversible and non-selective MAO inhibitors (MAOi\'s) were the first class of antidepressants, thus subsequent work on drugs such as the selective MAOA inhibitor clorgyline has focussed on selectivity and increased CNS penetration. MAOA is highly expressed in high grade and metastatic prostate cancer with a proposed effect on prostate cancer growth, recurrence, and drug resistance. A Phase II Clinical Trial has demonstrated the therapeutic effects of the irreversible nonselective MAOi phenelzine for prostate cancer. However, neurologic adverse effects led to early withdrawal in 25% of the enrolled patient-population. In this work, we revised the clorgyline scaffold with the goal of decreasing CNS penetration to minimize CNS-related side effects while retaining or enhancing MAOA inhibition potency and selectivity. Using the known co-crystal structure of clorgyline bound with FAD co-factor in the hMAOA active site as a reference, we designed and synthesized a series of compounds predicted to have lower CNS penetration (logBB). All synthesized derivatives displayed favorable drug-like characteristics such as predicted Caco-2 permeability and human oral absorption, and exhibited highly selective hMAOA binding interactions. Introduction of an HBD group (NH2 or OH) at position 5 of the phenyl ring clorgyline resulted in 3x more potent hMAOA inhibition with equivalent or better hMAOB selectivity, and similar prostate cancer cell cytotoxicity. In contrast, introduction of larger substituents at this position or at the terminal amine significantly reduced the hMAOA inhibition potency, attributed in part to a steric clash within the binding pocket of the MAOA active site. Replacement of the N-methyl group by a more polar, but larger 2-hydroxyethyl group did not enhance potency. However, introduction of a polar 2-hydroxy in the propyl chain retained the highly selective MAOA inhibition and cancer cell cytotoxicity of clorgyline while reducing its CNS score from 2 to 0. We believe that these results identify a new class of peripherally directed MAOIs that may allow safer therapeutic targeting of MAOA for a variety of anti-cancer and anti-inflammatory indications.
摘要：
单胺氧化酶(MAOA/MAOB)是已知在中枢神经系统(CNS)中神经递质调节中的作用的酶。不可逆和非选择性MAO抑制剂（MAOi）是第一类抗抑郁药，因此,关于选择性MAOA抑制剂clorgyline等药物的后续工作集中在选择性和增加CNS渗透上.MAOA在高级别和转移性前列腺癌中高表达，对前列腺癌的生长具有预期的影响，复发,和抗药性。II期临床试验已经证明了不可逆的非选择性MAOi苯乙嗪对前列腺癌的治疗效果。然而,在纳入的患者人群中,有25%的患者出现了神经系统不良反应导致患者提前戒断.在这项工作中,我们修改了Clorgyline支架,目的是减少CNS渗透,以最大限度地减少CNS相关副作用,同时保留或增强MAOA抑制效力和选择性.使用已知的与hMAOA活性位点中的FAD辅因子结合的Clorgyline的共晶体结构作为参考，我们设计并合成了一系列预测具有较低CNS渗透(logBB)的化合物。所有合成的衍生物都表现出良好的药物样特征，例如预测的Caco-2渗透性和人类口服吸收，并表现出高度选择性的hMAOA结合相互作用。在苯环clorgyline的5位引入HBD基团（NH2或OH）导致3倍更有效的hMAOA抑制，具有同等或更好的hMAOB选择性，和类似的前列腺癌细胞毒性。相比之下,在该位置或末端胺引入较大的取代基显著降低了hMAOA抑制效力，部分归因于MAOA活性位点的结合袋内的空间冲突。用极性更大的N-甲基取代，但较大的2-羟乙基并不能增强药效.然而,在丙基链中引入极性2-羟基保留了高选择性MAOA抑制和Clorgyline的癌细胞细胞毒性，同时将其CNS评分从2降低到0。我们相信,这些结果鉴定了一类新的外周定向的MAOI,其可以允许针对多种抗癌和抗炎适应症的MAOA的更安全的治疗靶向。
