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The Discovery of LML134, a Histamine H3 Receptor Inverse Agonist for the Clinical Treatment of Excessive Sleep Disorders
Author(s) -
Troxler Thomas,
Feuerbach Dominik,
Zhang Xuechun,
Yang Charles R.,
Lagu Bharat,
Perrone Mark,
Wang TieLin,
Briner Karin,
Bock Mark G.,
Auberson Yves P.
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900176
Subject(s) - inverse agonist , histamine h3 receptor , insomnia , sleep (system call) , agonist , histamine , pharmacology , receptor , disengagement theory , medicine , mechanism (biology) , chemistry , computer science , philosophy , gerontology , operating system , epistemology
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).
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