JNJ-55308942 is a high-affinity, selective, BBB (blood-brain barrier) permeable (penetrable) P2X7 functional antagonist (hP2X7: IC50=10 nM, Ki=7.1 nM; rP2X7: IC50=15 nM, Ki=2.9 nM). JNJ-55308942 is highly bioavailable orally, binds to brain P2X7 and blocks IL-1β release from adult rodent brains.

Physicochemical Properties

Molecular Formula	C17H12F5N7O
Molecular Weight	425.315499305725
Exact Mass	425.102
CAS #	2166558-11-6
PubChem CID	90408860
Appearance	White to light yellow solid powder
LogP	1.5
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	11
Rotatable Bond Count	2
Heavy Atom Count	30
Complexity	632
Defined Atom Stereocenter Count	1
SMILES	FC1C(C(F)(F)F)=NC=CC=1C(N1CC2=C(C[C@@H]1C)N(C1N=CC(=CN=1)F)N=N2)=O
InChi Key	LMDWZBQISRTEBH-QMMMGPOBSA-N
InChi Code	InChI=1S/C17H12F5N7O/c1-8-4-12-11(26-27-29(12)16-24-5-9(18)6-25-16)7-28(8)15(30)10-2-3-23-14(13(10)19)17(20,21)22/h2-3,5-6,8H,4,7H2,1H3/t8-/m0/s1
Chemical Name	[(6S)-1-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridin-5-yl]-[3-fluoro-2-(trifluoromethyl)pyridin-4-yl]methanone
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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.
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	P2X7 Receptor
ln Vitro	The pKi of the rat P2X7 channel and the recombinant human channel are 8.5 and 8.1, respectively, according to JNJ-55308942. In human blood, mouse blood, and microglia, JNJ-55308942 potently and concentration-dependently reduces the release of IL-1β [2].
ln Vivo	JNJ-55308942 (30 mg/kg; oral) reduces the activation of microglia in mice induced by LPS[2]. Oral JNJ-55308942 (30 mg/kg) treatment corrected BCG-induced sucrose preference and social interaction deficits in a model of depression generated by BCG. With an ED50 of 0.07 mg/kg, the chemical exhibited dose- and concentration-dependent occupancy of rat brain P2X7 following oral treatment. Target engagement has a functional influence on the brain of conscious rats, as demonstrated by the P2X7 antagonist (3 mg/kg, oral) which prevents the release of IL-1β in the brain caused by Bz-ATP[2]. F, Vss, CL, Cmax, and AUC24h values for JNJ-55308942 (5 mg/kg; po) are 81%, 1.7 L/kg, 3.7 mL min/kg, 1747 ng/mL, and 17549 (ng/mL) h, respectively[1].
Animal Protocol	Animal/Disease Models: Sixteen male C57/BL6J mice[2] Doses: 30 mg/kg Route of Administration: Po (after an ip injection of LPS (0.8 mg/kg, ip)) Experimental Results: Dramatically attenuated the effect of LPS on FSC, CD45 surface expression and CD11b surface expression. Animal/Disease Models: Rat[1] Doses: Po (pharmacokinetic/PK Analysis) Route of Administration: 5 mg/kg Experimental Results: The F, Vss, CL, Cmax and AUC24h were 81%, 1.7 L/kg, 3.7 mL min /kg, 1747 ng/mL, and 17549 (ng/mL) h, respectively.
References	[1]. Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia. Neuropsychopharmacology. 2018;43(13):2586-2596. [2]. A Dipolar Cycloaddition Reaction To Access 6-Methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate. J Med Chem. 2018;61(1):207-223.

Solubility Data

Solubility (In Vitro)

DMSO: 100 mg/mL (235.12 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 4 mg/mL (9.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 40.0 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: ≥ 4 mg/mL (9.40 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 40.0 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: ≥ 4 mg/mL (9.40 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 40.0 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	2.3512 mL	11.7559 mL	23.5117 mL
	5 mM	0.4702 mL	2.3512 mL	4.7023 mL
	10 mM	0.2351 mL	1.1756 mL	2.3512 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.