Auberson Yves P, Troxler Thomas, Zhang Xuechun, Yang Charles R, Fendt Markus, Feuerbach Dominik, Liu Yu-Chih, Lagu Bharat, Lerchner Andreas, Perrone Mark, Lei Lijun, Zhang Chao, Wang Chunxiu, Wang Tie-Lin, Bock Mark G
Novartis Institutes for BioMedical Research, Forum 1, Novartis Campus, 4056 Basel (Switzerland).
ChemMedChem. 2014 Aug;9(8):1683-96. doi: 10.1002/cmdc.201402055. Epub 2014 May 21.
Ergoline derivative (6aR,9R)-4-(2-(dimethylamino)ethyl)-N-phenyl-9-(pyrrolidine-1-carbonyl)-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-7(4H)-carboxamide (1), a CXCR3 antagonist, also inhibits human histamine H3 receptors (H3R) and represents a structurally novel H3R inverse agonist chemotype. It displays favorable pharmacokinetic and in vitro safety profiles, and served as a lead compound in a program to explore ergoline derivatives as potential drug candidates for the treatment of narcolepsy. A key objective of this work was to enhance the safety and efficacy profiles of 1, while minimizing its duration of action to mitigate the episodes of insomnia documented with previously reported clinical candidates during the night following administration. Modifications to the ergoline core at positions 1, 6 and 8 were systematically investigated, and derivative 23 (1-((4aR,8R,9aR)-8-(hydroxymethyl)-1-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)-4,4a,7,8,9,9a-hexahydroindolo[1,14-fg]quinolin-6(1H)-yl)ethanone) was identified as a promising lead compound. Derivative 23 has a desirable pharmacokinetic profile and demonstrated efficacy by enhancing brain concentrations of tele-methylhistamine, a major histamine metabolite. This validates the potential of the ergoline scaffold to serve as a template for the development of H3R inverse agonists.
麦角灵衍生物(6aR,9R)-4-(2-(二甲基氨基)乙基)-N-苯基-9-(吡咯烷-1-羰基)-6,6a,8,9-四氢吲哚并[4,3-fg]喹啉-7(4H)-甲酰胺(1)，一种CXCR3拮抗剂，也抑制人组胺H3受体(H3R)，代表一种结构新颖的H3R反向激动剂化学类型。它具有良好的药代动力学和体外安全性，是探索麦角灵衍生物作为发作性睡病潜在候选药物项目中的先导化合物。这项工作的一个关键目标是提高1的安全性和有效性，同时尽量缩短其作用持续时间，以减轻先前报道的临床候选药物给药后夜间出现的失眠发作。系统研究了麦角灵核心在1、6和8位的修饰，衍生物23(1-((4aR,8R,9aR)-8-(羟甲基)-1-(2-((R)-2-甲基吡咯烷-1-基)乙基)-4,4a,7,8,9,9a-六氢吲哚并[1,14-fg]喹啉-6(1H)-基)乙酮)被确定为一种有前景的先导化合物。衍生物23具有理想的药代动力学特征，并通过提高主要组胺代谢物远甲基组胺的脑浓度证明了其有效性。这验证了麦角灵骨架作为H3R反向激动剂开发模板的潜力。
