JNJ-42153605 is a potent, selective and allosteric modulator of the mGlu2 (metabotropic glutamate 2) receptor with with an EC50 of 17 nM. It exhibits a superior pharmacokinetic profile in both rodent and nonrodent variants. It is determined that JNJ-42153605 is not an agonist or antagonist toward other mGlu receptor subtypes up to 30 μM when its selectivity for the mGlu2 receptor is evaluated. With no signs of P-glycoprotein efflux, JNJ-42153605 exhibits high permeability. Using a dose of 3 mg/kg po in the rat sleep-wake EEG paradigm, JNJ-42153605 demonstrated a central in vivo efficacy by inhibiting the REM sleep state, a phenomenon previously demonstrated to be mGlu2 mediated. Using an ED₩₀ of 5.4 mg/kg sc, which is suggestive of antipsychotic activity, JNJ-42153605 reversed PCP-induced hyperlocomotionin mice.

Physicochemical Properties

Molecular Formula	C₂₂H₂₃F₃N₄
Molecular Weight	400.44
Exact Mass	400.187
Elemental Analysis	C, 65.99; H, 5.79; F, 14.23; N, 13.99
CAS #	1254977-87-1
Related CAS #	1254977-87-1
PubChem CID	49765871
Appearance	White to off-white solid powder
LogP	5.149
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	4
Heavy Atom Count	29
Complexity	553
Defined Atom Stereocenter Count	0
SMILES	FC(C1=C(N2CCC(C3=CC=CC=C3)CC2)C=CN4C1=NN=C4CC5CC5)(F)F
InChi Key	BQAVZGJJQFJSMW-UHFFFAOYSA-N
InChi Code	InChI=1S/C22H23F3N4/c23-22(24,25)20-18(10-13-29-19(14-15-6-7-15)26-27-21(20)29)28-11-8-17(9-12-28)16-4-2-1-3-5-16/h1-5,10,13,15,17H,6-9,11-12,14H2
Chemical Name	3-(cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine
Synonyms	JNJ-42153605; JNJ 42153605; JNJ42153605
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	mGluR2 ( EC50 = 17 nM )
ln Vitro	In vitro activity: JNJ-42153605 is discovered to exhibit no or very little affinity or activity at any of the targets in the CEREP panel of receptors (>100-fold selectivity for mGlu2 receptor) and to have no agonist or antagonist activity toward other mGlu receptor subtypes up to 30 μM (>50-fold vs mGluR2)[1].
ln Vivo	JNJ-42153605, with an ED50 of 5.4 mg/kg sc, significantly and dose-dependently reduces the increase in locomotor activity in mice induced by phencyclidine (PCP, 5 mg/kg sc). JNJ-42153605 exhibits a quick rate of absorption from the digestive system, taking 0.5 hours to reach its maximum concentration. In both rats and dogs, clearance in vivo ranges from moderate to high (35 and 29 mL/min/kg, respectively). Across all species, elimination halflives are relatively short, ranging from 2.7 hours in rats to 0.8–1.1 hours in dogs. The distribution volume is marginally greater than the total amount of water in the body, suggesting distribution outside the plasma. In all species, bioavailability ranges from low to moderate (35% in rats and 18–33% in dogs)[1].
Animal Protocol	Rats: In 16 rats, the effects of the tested molecule and vehicle on sleep-wake distribution are examined during the lights-on period. Two EEG recording sessions are conducted: the first one begins at 13:30 and lasts for 20 hours after saline is administered orally. The second recording session is conducted for the same amount of time at the same consecutive circadian time after the administration of JNJ-42153605 or the vehicle (20% CD+2H2T). Mice: Male NMRI mice are given either vehicle or JNJ-42153605 as a treatment, and then they are put separately into open fields for 30 minutes after being challenged with either PCP (5.0 mg/kg, sc) or vehicle. Computerized analysis systems and video tracking are used to measure the distance that animals travel.
References	[1]. 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. J Med Chem. 2012 Oct 25;55(20):8770-89.

Solubility Data

Solubility (In Vitro)

DMSO: 4~16.7 mg/mL (10.0~41.6 mM) Water: <1 mg/mL Ethanol: ~10 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: 1.67 mg/mL (4.17 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.67 mg/mL (4.17 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 1.67 mg/mL (4.17 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.4973 mL	12.4863 mL	24.9725 mL
	5 mM	0.4995 mL	2.4973 mL	4.9945 mL
	10 mM	0.2497 mL	1.2486 mL	2.4973 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.