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Cover Picture: Discovery of [(2 R ,5 R )‐5‐{[(5‐Fluoropyridin‐2‐yl)oxy]methyl}‐2‐methylpiperidin‐1‐yl][5‐methyl‐2‐(pyrimidin‐2‐yl)phenyl]methanone (MK‐6096): A Dual Orexin Receptor Antagonist with Potent Sleep‐Promoting Properties (ChemMedChem 3/2012)
Author(s) -
Coleman Paul J.,
Schreier John D.,
Cox Christopher D.,
Breslin Michael J.,
Whitman David B.,
Bogusky Michael J.,
McGaughey Georgia B.,
Bednar Rodney A.,
Lemaire Wei,
Doran Scott M.,
Fox Steven V.,
Garson Susan L.,
Gotter Anthony L.,
Harrell C. Meacham,
Reiss Duane R.,
Cabalu Tamara D.,
Cui Donghui,
Prueksaritat Thomayant,
Stevens Joanne,
Tannenbaum Pamela L.,
Ball Richard G.,
Stellabott Joyce,
Young Steven D.,
Hartman George D.,
Winrow Christopher J.,
Renger John J.
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Reports
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201290006
Subject(s) - piperidine , wakefulness , orexin , chemistry , pharmacology , neuropeptide , stereochemistry , electroencephalography , receptor , neuroscience , medicine , psychology , biochemistry
The cover picture shows orexin neuronal pathways that project from the lateral hypothalamus into regions of the brain that modulate wakefulness. Blockade of this neuropeptide signaling pathway with small‐molecule receptor antagonists is a clinically validated approach to the treatment of sleep disorders. The discovery and synthesis of MK‐6096 is described in the Full Paper by Paul J. Coleman et al. on p. 415 ff. MK‐6096 has as a central core, a piperidine carboxamide with two axial substituents on the piperidine ring. This configuration is essential for high receptor potency and is potentiated by α ‐methyl substitution on the piperidine ring. MK‐6096 is brain penetrant and highly potent in dose‐dependently promoting sleep in preclinical electroencephalography (EEG) models.