CTEP: A Novel, Potent, Long-Acting, and Orally Bioavailable Metabotropic Glutamate Receptor 5 Inhibitor

Lothar Lindemann; Georg Jaeschke; Aubin Michalon; Eric Vieira; Michael Honer; Will Spooren; Richard Porter; Thomas Hartung; Sabine Kolczewski; Bernd Büttelmann; Christophe Flament; Catherine Diener; Christophe Fischer; Silvia Gatti; Eric P. Prinssen; Neil Parrott; Gerhard Hoffmann; Joseph G. Wettstein

doi:10.1124/jpet.111.185660

Abstract

The metabotropic glutamate receptor 5 (mGlu5) is a glutamate-activated class C G protein-coupled receptor widely expressed in the central nervous system and clinically investigated as a drug target for a range of indications, including depression, Parkinson's disease, and fragile X syndrome. Here, we present the novel potent, selective, and orally bioavailable mGlu5 negative allosteric modulator with inverse agonist properties 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP). CTEP binds mGlu5 with low nanomolar affinity and shows >1000-fold selectivity when tested against 103 targets, including all known mGlu receptors. CTEP penetrates the brain with a brain/plasma ratio of 2.6 and displaces the tracer [³H]3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-methyl-oxime (ABP688) in vivo in mice from brain regions expressing mGlu5 with an average ED₅₀ equivalent to a drug concentration of 77.5 ng/g in brain tissue. This novel mGlu5 inhibitor is active in the stress-induced hyperthermia procedure in mice and the Vogel conflict drinking test in rats with minimal effective doses of 0.1 and 0.3 mg/kg, respectively, reflecting a 30- to 100-fold higher in vivo potency compared with 2-methyl-6-(phenylethynyl)pyridine (MPEP) and fenobam. CTEP is the first reported mGlu5 inhibitor with both long half-life of approximately 18 h and high oral bioavailability allowing chronic treatment with continuous receptor blockade with one dose every 48 h in adult and newborn animals. By enabling long-term treatment through a wide age range, CTEP allows the exploration of the full therapeutic potential of mGlu5 inhibitors for indications requiring chronic receptor inhibition.

Footnotes

All financial support for this work has been provided by F. Hoffmann-La Roche Ltd.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.111.185660.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
CNS
central nervous system
CTEP
2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine
DAT
dopamine transporter
GABA
γ-aminobutyric acid
GTPγS
guanosine 5′-O-(3-thio)triphosphate
CHO
Chinese hamster ovary
HEK
human embryonic kidney
HPLC
high-performance liquid chromatography
IP
inositol phosphate
L-AP4
(2S)-2-amino-4-phosphonobutanoic acid
mGlu
metabotropic glutamate
MPEP
2-methyl-6-(phenylethynyl)pyridine
MS
mass spectrometry
MTEP
3-((2-methyl-4-thiazolyl)ethynyl)pyridine
NET
norepinephrine transporter
NMDA
N-methyl-d-aspartate
NK
neurokinin
SERT
serotonin transporter
SIH
stress-induced hyperthermia
B/P
brain/plasma
DMSO
dimethyl sulfoxide
ABP688
3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-methyl-oxime
LY341495
2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-d-alanine
SR142801
(S)-N-(1-{3-[(3R)-1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]propyl}-4-phenylpiperidin-4-yl-N-methylacetamide
WIN35,428
2β-carbomethoxy-3β-(4-fluorophenyl)tropane
SCH 23390
R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
SR48968
N-[(2S)-4-(4-acetamido-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide
G418
(2R,3S,4R,5R,6S)-5-amino-6-[(1R,2S,3S,4R,6S)-4,6-diamino-3-[(2R,3R,4R,5R)-3,5-dihydroxy-5-methyl-4-methylaminooxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-2-(1-hydroxyethyl)oxane-3,4-diol
LY354740
(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid
SIB-1757
6-methyl-2-(phenylazo)-3-pyridinol
SIB-1893
(E)-2-methyl-6-(2-phenylethenyl)pyridine.