2. Academic Validation
  3. The Discovery of LML134, a Histamine H3 Receptor Inverse Agonist for the Clinical Treatment of Excessive Sleep Disorders

The Discovery of LML134, a Histamine H3 Receptor Inverse Agonist for the Clinical Treatment of Excessive Sleep Disorders

  • ChemMedChem. 2019 Jul 3;14(13):1238-1247. doi: 10.1002/cmdc.201900176.
Thomas Troxler 1,  Dominik Feuerbach 1,  Xuechun Zhang 2,  Charles R Yang 3,  Bharat Lagu 4,  Mark Perrone 4,  Tie-Lin Wang 2,  Karin Briner 4,  Mark G Bock 4,  Yves P Auberson 1
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, Novartis Pharma AG, Klybeckstrasse 141, 4057, Basel, Switzerland.
  • 2 ChemPartner, 998 Halei Road, Zhangjiang Hi-Tech Park Pudong New Area, Shanghai, 201203, China.
  • 3 ShangPharma Innovation Inc., 280 Utah Avenue, South San Francisco, CA, 94080, USA.
  • 4 Novartis Institutes for BioMedical Research, Novartis Pharma AG, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA.
PMID: 30957954 DOI: 10.1002/cmdc.201900176
Abstract

Histamine H3 receptor (H3R) inverse agonists that have been in clinical trials for the treatment of excessive sleep disorders, have been plagued with insomnia as a mechanism-based side effect. We focused on the identification of compounds that achieve high receptor occupancy within a short time, followed by rapid disengagement from the receptor, a target profile that could provide therapeutic benefits without the undesired side effect of insomnia. This article describes the optimization work that led to the discovery of 1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl 4-cyclobutylpiperazine-1-carboxylate (18 b, LML134).

Keywords

H3 receptor; carbamate; histamine; medicinal chemistry; neurotransmitters.

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