Navacaprant (BTRX-335140) is a selective, orally bioactive κ opioid receptor (KOR) antagonist (inhibitor) with antagonistic activity against κOR, μOR and δOR with IC50s of 0.8 nM, 110 nM and 6500 nM, respectively. Navacaprant has favorable in vitro ADMET and in vivo pharmacokinetic profiles in rats. Navacaprant distributes well into the CNS and may be utilized in neuropathy studies.

Physicochemical Properties

Molecular Formula	C25H32FN5O2
Molecular Weight	453.552289009094
Exact Mass	453.254
CAS #	2244614-14-8
PubChem CID	137434175
Appearance	Off-white to light yellow solid powder
LogP	4.7
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	5
Heavy Atom Count	33
Complexity	630
Defined Atom Stereocenter Count	0
SMILES	FC1=CC(CC)=CC2=C1N=C(C(C1=NC(C)=NO1)=C2C)N1CCC(CC1)NC1CCOCC1
InChi Key	CQOJHAJWCDJEAT-UHFFFAOYSA-N
InChi Code	InChI=1S/C25H32FN5O2/c1-4-17-13-20-15(2)22(25-27-16(3)30-33-25)24(29-23(20)21(26)14-17)31-9-5-18(6-10-31)28-19-7-11-32-12-8-19/h13-14,18-19,28H,4-12H2,1-3H3
Chemical Name	1-[6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl]-N-(oxan-4-yl)piperidin-4-amine
Synonyms	BTRX335140; BTRX 335140; BTRX-335140
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

ln Vitro	At Kappa opioid receptors, navacaprant (BTRX-335140) (0-10 μM; 4 hours) demonstrates selective antagonist action [1].
ln Vivo	Navacaprant (BTRX-335140) (0.01-3 mg/kg; once oral) lowers plasma prolactin secretion triggered by U69,593 to levels not induced by U69,593 [1]. When administered intraperitoneally, navacaprant (BTRX-335140) (1 mg/kg) inhibits the analgesic action of hot water due to U-50488 [1]. 1.19 BTRX-335140 pharmacokinetic properties in rodents [1]. AUC0-t (h• ng/mL) 153 725 265 232 Vss (L/kg) 13.8 7.72 F (%) 30.2 12 Rat IV 1 mg/kg, Mouse IV 3 mg/kg, Rat PO 5 mg/kg, and Mouse PO 10 mg/kg CL (mL/min/kg) 105 66.5 t1/2 (h) 1.81 1.91 6.19 2.57
Cell Assay	Cell viability assay [1] Cell Types: OPRK1-BLA U2OS Cell Tested Concentrations: 0-10 μM Incubation Duration: 4 hrs (hours) Experimental Results: demonstrated antagonistic activity against KOR, DOR and MOR, with IC50 values of 0.8, 110 and 6500 nM respectively, and Displays selective antagonistic activity of KOR.
Animal Protocol	Animal/Disease Models: Rat PRL model [1] Doses: 0.01, 0.03, 0.1, 0.3, 1 and 3 mg /kg Route of Administration: po (oral gavage); 0.01-3 mg/kg Primary Experimental Results:Even at a dose of 0.1 mg/kg, it can effectively reduce the high level of prolactin caused by U69,593. Animal/Disease Models: Adult male ICR mice, tail immersed in 50°C hot water [1] Doses: 1 mg/kg Route of Administration: intraperitoneal (ip) injection; 1 mg/kg Primary Experimental Results:Resistance during 1 hour instead of 24 hrs (hrs (hours)) of pretreatment blocked U-50488-induced analgesia and demonstrated drug-like duration of action in blocking KOR.
References	[1]. Design and Synthesis of a Novel and Selective Kappa Opioid Receptor (KOR) Antagonist (BTRX-335140). J Med Chem. 2019 Feb 28;62(4):1761-1780.
Additional Infomation	BTRX-335140 is under investigation in clinical trial NCT04221230 (Study in Major Depressive Disorder With BTRX-335140 vs Placebo).

Solubility Data

Solubility (In Vitro)

DMSO : ~3.85 mg/mL (~8.49 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 1.67 mg/mL (3.68 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. Solubility in Formulation 2: ≥ 1 mg/mL (2.20 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 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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 3: ≥ 1 mg/mL (2.20 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 10.0 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.2048 mL	11.0241 mL	22.0483 mL
	5 mM	0.4410 mL	2.2048 mL	4.4097 mL
	10 mM	0.2205 mL	1.1024 mL	2.2048 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.