AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders
AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders
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DOI：
10.3233/jad-151146
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发表时间：
2016-01-01
影响因子：
4
通讯作者：
Okun, Ilya
中科院分区：
文献类型：
--
作者：
Ivachtchenko, Alexandre V.;Lavrovsky, Yan;Okun, Ilya
许多新的高选择性和特异性候选药物在治疗病因不明或复杂的疾病方面缺乏疗效，许多中枢神经系统(CNS)疾病也是如此，这鼓励了开发多模式(多靶点)药物的想法。在这篇手稿中，我们描述了多模式候选药物AVN-101的分子药理学、体外ADME、在动物和人类中的药代动力学(I期临床研究的一部分)、生物分布、生物利用度、体内疗效和安全性。我们已经进行了具有多靶点作用机制的下一代候选药物的开发，用于治疗中枢神经系统疾病。AVN-101是一种很强的5-HT7受体拮抗剂(Ki=153 pm)，对5-HT6、5-HT2A和5-HT2C受体的作用略弱(Ki=1.2-2.0 nM)。AVN-101对组胺H1(Ki=0.58 nM)和肾上腺素能α2A、α2B和α2C(Ki=0.41-3.6 nM)受体也表现出较高的亲和力。在中枢神经系统疾病动物模型中，AVN-101具有良好的口服生物利用度和促进脑-血屏障通透性，毒性低，疗效合理。I期临床研究表明，AVN-101在每天口服剂量高达20毫克时耐受性良好。它不会显著影响血浆和尿液生化，也不会延长QT间期，因此安全性较低。将在临床试验中测试的AVN-101的主要治疗领域将是阿尔茨海默病。然而，由于其抗焦虑和抗抑郁的活性，它也有很强的理由也被研究用于诸如广泛性焦虑症、抑郁症、精神分裂症和多发性硬化症等疾病。
Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Ki = 153 pM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-(2C) receptors (Ki = 1.2-2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic alpha 2A, alpha 2B, and alpha 2C (Ki = 0.41-3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer's disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis.