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Ergoline-derived Inverse Agonists of the Human H3-Receptor for the Treatment of Narcolepsy

Auberson, Yves, Troxler, Thomas J., Zhang, Xuechun, Yang, Charles, Fendt, Markus, Feuerbach, Dominik, Liu, Yu-Chih, Lagu, Bharat, Lerchner, Andreas, Perrone, Mark, Lei, Lijun, Zhang, Chao, Wang, Chunxiu, Wang, Tie-Lin and Bock, Mark (2014) Ergoline-derived Inverse Agonists of the Human H3-Receptor for the Treatment of Narcolepsy. ChemMedChem. ISSN 18607179


Ergoline derivative 1, a CXCR3 antagonist, also inhibits human histamine H3-receptors (H3-R), and represents a structurally novel H3-R 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. 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 H3-R inverse agonists.

Item Type: Article
Keywords: Histamine H3; ergoline; inverse agonist; narcolepsy
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46


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