Discovery and Development of 1-[(2-Bromophenyl)sulfony1]-5methoxy-3-[(4-methyl-1-piperazinyl)methy1]-1H-indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT6) Receptor Antagonist for Potential Treatment of Alzheimer's Disease
Discovery and Development of 1-[(2-Bromophenyl)sulfony1]-5methoxy-3-[(4-methyl-1-piperazinyl)methy1]-1H-indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT6) Receptor Antagonist for Potential Treatment of Alzheimer's Disease
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DOI：
10.1021/acs.jmedchem.6b01662
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发表时间：
2017-03-09
影响因子：
7.3
通讯作者：
Jasti, Venkat
中科院分区：
文献类型：
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作者：
Nirogi, Ramakrishna;Shinde, Anil;Jasti, Venkat
优化了一系列新的3-（哌嗪基甲基）吲哚衍生物作为5-羟色胺-6受体（5-HT6R）拮抗剂，鉴定了1[（2-溴苯基）磺酰基]-5-甲氧基-3-[（4-甲基-1-哌嗪基）甲基]- 1h -吲哚]- 1h -吲哚二烷基酯一水合物（Sal, SUVN-502）作为潜在治疗认知障碍的临床候选药物。它对人5-HT6R具有高亲和力（K-i = 2.04 nM），对受体、酶、多肽、生长因子、离子通道、类固醇、免疫因子、第二信使和前列腺素等100多个靶点具有选择性。它对5-HT2A受体具有高选择性。它是口服生物可利用性和脑渗透，具有强大的临床前疗效。Sal、多奈哌齐和美金刚联合（三联用药）对海马腹侧细胞外乙酰胆碱水平产生协同作用。三联疗法的临床前疗效和对5-HT2A受体的高选择性是其与众不同的特点，最终选择了Sal进行进一步的开发。第一阶段的安全性和药代动力学评估已经完成，允许启动第二阶段的概念验证研究。
Optimization of a novel series of 3-(piperazinylmethyl) indole derivatives as 5-hydroxytryptamine-6 receptor (5-HT6R) antagonists resulted in identification of 1[(2-bromophenyl)sulfony1]-5-methoxy-3-[ (4-methyl1-1-piperazinyl)methyl]-1H-indole]-1H-indole dimesylate monohydrate (Sal, SUVN-502) as a clinical candidate for potential treatment of cognitive disorders. It has high affinity at human 5-HT6R(K-i = 2.04 nM) and selectivity over 100 target sites which include receptors, enzymes, peptides, growth factors, ion channels, steroids, immunological factors, second messengers, and prostaglandins. It has high selectivity over 5-HT2A receptor. It is orally bioavailable and brain penetrant with robust preclinical efficacy. The combination of Sal, donepezil, and memantine (triple combination) produces synergistic effects in extracellular levels of acetylcholine in the ventral hippocampus. Preclinical efficacy in triple combination and high selectivity over 5-HT2A receptors are the differentiating features which culminated in selection of Sal for further development. The Phase-1 evaluation of safety and pharmacokinetics has been completed, allowing for the initiation of a Phase-2 proof of concept study.