Ergoline-derived inverse agonists of the human h3 receptor for the treatment of narcolepsy.

Abstract

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.

• Authors: Yves P Auberson, Thomas Troxler, Xuechun Zhang, Charles R Yang, Markus Fendt, Dominik Feuerbach, Yu-Chih Liu, Bharat Lagu, Andreas Lerchner, Mark Perrone, Lijun Lei, Chao Zhang, Chunxiu Wang, Tie-Lin Wang, Mark G Bock
• Journal: ChemMedChem (ChemMedChem) Vol. 9 Issue 8 Pg. 1683-96 (Aug 2014) ISSN: 1860-7187 [Electronic] Germany
• PMID: 24850792 (Publication Type: Journal Article)
• Copyright: © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• 1-(8-(hydroxymethyl)-1-(2-(2-methylpyrrolidin-1-yl)ethyl)-4,4a,7,8,9,9a-hexahydroindolo(1,14-fg)quinolin-6(1H)-yl)ethanone
• Ergolines
• Histamine Agonists
• Receptors, Histamine H3

Topics

• Animals
• Caco-2 Cells
• Cell Line
• Dogs
• Drug Inverse Agonism
• Ergolines (chemistry, pharmacokinetics, therapeutic use)
• Half-Life
• Histamine Agonists (chemistry, pharmacokinetics, therapeutic use)
• Humans
• Madin Darby Canine Kidney Cells
• Male
• Mice
• Microsomes, Liver (metabolism)
• Narcolepsy (drug therapy)
• Protein Binding
• Rats
• Rats, Sprague-Dawley
• Receptors, Histamine H3 (chemistry, metabolism)
• Structure-Activity Relationship