Discovery of 3-cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine (JNJ-42153605): a positive allosteric modulator of the metabotropic glutamate 2 receptor.
Advanced leads from a series of 1,2,4-triazolo[4,3-a]pyridines with mGlu2 receptor PAM activity are reported. By modification of the analogous imidazo[1,2-a]pyridine series, the newly reported leads have improved potency, in vitro ADMET, and hERG as well as good in vivo PK profile. The optimization of the series focused on improving metabolic stability while controlling lipophilicity by introducing small modifications to the scaffold substituents. Analysis of this series combined with our previously reported mGlu2 receptor PAMs showed how lipophilic ligand efficiency was improved during the course of the program. Among the best compounds, example 20 (JNJ-42153605) showed a central in vivo efficacy by inhibition of REM sleep state at a dose of 3 mg/kg po in the rat sleep-wake EEG paradigm, a phenomenon shown earlier to be mGlu2 mediated. In mice, compound 20 reversed PCP-induced hyperlocomotion with an ED₅₀ of 5.4 mg/kg sc, indicative of antipsychotic activity.
Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A., Jarama 75, 45007 Toledo, Spain. jcid@its.jnj.com
Jose María
JM
Cid
Gary
G
Tresadern
Juan Antonio
JA
Vega
Ana Isabel
AI
de Lucas
Encarnación
E
Matesanz
Laura
L
Iturrino
María Lourdes
ML
Linares
Aránzazu
A
Garcia
José Ignacio
JI
Andrés
Gregor J
GJ
Macdonald
Daniel
D
Oehlrich
Hilde
H
Lavreysen
Anton
A
Megens
Abdellah
A
Ahnaou
Wilhelmus
W
Drinkenburg
Claire
C
Mackie
Stefan
S
Pype
David
D
Gallacher
Andrés A
AA
Trabanco
D000494:Allosteric Regulation; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D004569:Electroencephalography; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D006948:Hyperkinesis / Q000188:drug therapy; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017286:Polysomnography; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014851:Wakefulness / Q000187:drug effects
C577930:3-cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl(1,2,4)triazolo(4,3-a)pyridine; D014150:Antipsychotic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D014227:Triazines; C108822:metabotropic glutamate receptor 2