TRPV1 (transient receptor potential vanilloid 1) antagonist
Human TRPV1 (hTRPV1): IC₅₀ = 4.6 nM in capsaicin-induced Ca²⁺ influx assay; Ki = 6.5 nM for [[³H]](+)-resiniferatoxin binding; IC₅₀ = 23 nM for capsaicin-induced activation; IC₅₀ = 6.8 nM for pH-induced activation; 74% inhibition of heat-evoked currents at 0.1 µM.
Rat TRPV1 (rTRPV1): IC₅₀ = 21 nM in capsaicin-induced Ca²⁺ influx assay.
No activity against TRPM8, TRPV2, or TRPA1 at concentrations up to 10 µM.[1]

In HEK293 cells expressing TRPV1 channels, mavatrep (a series of decreasing doses commencing at 1 μM; 25 minutes) suppresses the Ca2+ influx caused by capsaicin [1].

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In a recombinant human TRPV1 functional assay using HEK293 cells, Mavatrep inhibited capsaicin-induced Ca²⁺ influx with an IC₅₀ of 4.6 nM.[1]
In whole-cell patch clamp electrophysiology studies, Mavatrep blocked capsaicin-induced (1 µM) and pH-induced (pH 5.0) activation of hTRPV1 in a concentration-dependent manner with IC₅₀ values of 23 nM and 6.8 nM, respectively.[1]
At 0.1 µM, Mavatrep produced 74 ± 8.1% inhibition of heat-evoked currents mediated by hTRPV1.[1]
In metabolic stability studies using rat and human liver microsomes, 93% and 100% of Mavatrep remained after 10 min incubation, respectively.[1]
Mavatrep showed minimal inhibition of CYP isoforms 3A4, 1A2, and 2D6 (IC₅₀ > 25 µM) in human liver microsomes.[1]
No significant inhibition (>50% at 1 µM) was observed in a panel of 50 GPCR and ion channel binding assays, 190 kinase assays, or in a recombinant hERG channel binding assay (10 µM).[1]

Mavatrep (0.1, 0.3, 1, 3, 10 mg/kg; oral; single dosage) exhibits complete reversal of pain in the carrageenan inflammation model and thermal hypersensitivity in the CFA pain inflammation model [1]. In rats, Mavatrep (10 mg/kg; oral; single dosage) shows a notable bioavailability of 51% [1].

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In the complete Freund’s adjuvant (CFA)-induced thermal hypersensitivity model in rats, oral administration of Mavatrep (10 mg/kg) produced significant reversal of hypersensitivity starting at 30 min and lasting for at least 3 h.[1]
The ED₅₀ and ED₉₀ values for reversal of CFA-induced thermal hypersensitivity were 1.8 mg/kg and 7.8 mg/kg, respectively, corresponding to plasma concentrations of 41.9 ng/mL and 270.8 ng/mL.[1]
In the carrageenan-induced thermal hypersensitivity model, Mavatrep exhibited ED₅₀ and ED₉₀ values of 0.18 mg/kg and 0.48 mg/kg, respectively, with corresponding plasma levels of 3.8 ng/mL and 9.2 ng/mL.[1]
Mavatrep reversed thermal hypersensitivity to a similar extent as celecoxib (30 mg/kg) in the CFA model.[1]
Oral administration of Mavatrep at 100 mg/kg induced a transient increase in core body temperature in rats (peak +0.86°C at 30 min), which returned to baseline within 1.5 h.[1]
No significant hemodynamic or ECG changes were observed in anesthetized guinea pigs at cumulative intravenous doses up to 10 mg/kg.[1]
No substantial behavioral or physiological effects were observed in rats following single oral doses of 30 or 300 mg/kg over a 14-day observation period.[1]

The binding affinity of Mavatrep for hTRPV1 was assessed using a radioligand competition assay with [[³H]](+)-resiniferatoxin. Membrane preparations from TRPV1-expressing cells were incubated with the radioligand and varying concentrations of Mavatrep to determine Ki values.[1]
Cytochrome P450 inhibition assays were conducted using human liver microsomes incubated with probe substrates for CYP3A4, CYP1A2, and CYP2D6 in the presence of Mavatrep to evaluate potential drug–drug interactions.[1]

Cell viability assay [1]
Cell Types: HEK293 cells (stably expressing TRPV1 channel)
Tested Concentrations: A series of decreasing concentrations starting from 1 μM
Incubation Duration: 25 minutes
Experimental Results: Inhibited capsaicin-induced Ca2+ influx, IC50 value was 4.6 nM.

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TRPV1 functional assays were performed using HEK293 cells stably expressing human or rat TRPV1. Cells were loaded with a Ca²⁺-sensitive fluorescent dye and exposed to test compounds before stimulation with capsaicin. Intracellular Ca²⁺ flux was measured using FLIPR or FDSS systems to determine IC₅₀ values.[1]
Electrophysiological studies were conducted using whole-cell patch clamp recordings on hTRPV1-HEK293 cells. Cells were exposed to capsaicin, acidic pH, or heat stimuli in the presence or absence of Mavatrep to assess channel blockade.[1]
Metabolic stability was evaluated by incubating Mavatrep with rat or human liver microsomes for 10 min, followed by quantification of the remaining compound.[1]

Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat (195-350 g; CFA pain inflammation model) [1].
Doses: 10 mg/kg
Route of Administration: po (po (oral gavage)) single dose.
Experimental Results: Significant reversal of CFA-induced thermal hypersensitivity, which started 30 minutes after administration and lasted for at least 3 hrs (hrs (hours)).

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Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat (195-350 g; CFA pain inflammation model) [1].
Doses: 1, 3, 10, 30 mg/kg
Route of Administration: po (po (oral gavage)) single dose.
Experimental Results: The thermal hypersensitivity reaction was completely reversed, with ED50 and ED80 values of 1.8 and 7.8 mg/kg, respectively, and corresponding plasma levels of 41.9 and 270.8 ng/mL, respectively.

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Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat (195-350 g; carrageenan inflammatory pain model) [1].
Doses: 0.1, 0.3, 1, 3, 10 mg/kg
Route of Administration: po (po (oral gavage)) single dose.
Experimental Results: The thermal hypersensitivity reaction induced by carrageenan was completely reversed, with ED50 and ED80 values of 0.18 and 0.48 mg/kg, respectively, and the corresponding plasma levels were 3.8

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For the CFA-induced inflammatory pain model, male Sprague-Dawley rats received an intraplantar injection of CFA (100 µL, 1:1 in saline). Thermal hypersensitivity was assessed 24 h later using a radiant heat stimulus. Test compounds were administered orally, and withdrawal latencies were measured at multiple time points post-dosing.[1]
For the carrageenan-induced inflammatory pain model, rats received an intraplantar injection of λ-carrageenan (200 µL, 10 mg/mL). Thermal hypersensitivity was assessed 3 h later, and compounds were administered orally prior to testing.[1]
Core body temperature studies were conducted in male Sprague-Dawley rats implanted with telemetry probes. Animals were administered Mavatrep orally (0.1–100 mg/kg), and temperature was recorded before and at scheduled intervals after dosing.[1]
A subchronic temperature study involved daily oral administration of Mavatrep (10 mg/kg) for 5 days, with core temperature measured before and after dosing each day.[1]
For pharmacokinetic studies, Mavatrep was administered intravenously (2 mg/kg) or orally (10 mg/kg) as a sodium salt solution in 20% hydroxypropyl-β-cyclodextrin to rats, dogs, monkeys, and mice. Blood samples were collected at various time points for plasma concentration analysis.[1]

In rats, mavatrep showed moderate clearance (33 mL/min/kg), a volume of distribution of 3.4 L/kg, and an oral bioavailability of 51%. [1] In dogs, it showed high clearance (29 mL/min/kg) and an oral bioavailability of 25%. [1] In monkeys, it showed low clearance (7 mL/min/kg) and an oral bioavailability of 70%. [1] In mice, it showed low clearance (10.5 mL/min/kg) and an oral bioavailability of 83%. [1] The half-life after oral administration was 1.3 hours in dogs and 5.8 hours in mice. [1] Its metabolic stability in human liver microsomes was high (100% retained after 10 minutes), moderate in rats (93%), and low in dogs (36%). [1]

Mavatrep induces a transient increase in core body temperature in rats in a dose-dependent manner, with a mean maximum increase of 1.18 ± 0.21°C observed after repeated administration (10 mg/kg/day for 5 consecutive days). No tolerance to this effect was observed. [1]
No significant inhibition of hERG channel binding was observed at a concentration of 10 µM. [1]
In guinea pigs, no significant hemodynamic or electrocardiographic effects were observed at intravenous doses up to 10 mg/kg. [1]
In general observational tests, no changes in core body temperature were observed 1 hour or 4 hours after a single oral administration of 30 or 300 mg/kg. [1]
This compound exhibits good selectivity for a variety of G protein-coupled receptors (GPCRs), ion channels, and kinases. [1]

[1]. Benzo [d] imidazole Transient Receptor Potential Vanilloid 1 Antagonists for the Treatment of Pain: Discovery of trans-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1 H-benzimidazol-5-yl}-phenyl)-propan-2-ol (Mavatrep). Journal of medic.

Mavatrep has been used in clinical trials to study the treatment of knee osteoarthritis. Mavatrep is a selective, high-affinity TRPV1 receptor antagonist developed specifically for the treatment of pain, particularly inflammatory and neuropathic pain. [1] It was initially developed with a biarylamide backbone, but was later modified to benzimidazole-based structures with the introduction of trans-vinyl linkers and optimized head- and tail substituents to improve its potency and metabolic stability. [1] The compound has shown significant oral efficacy in preclinical pain models, even at low plasma concentrations, and is currently in Phase II clinical trials. [1] Its thermal effects are mild and transient, and no other systemic toxicities were observed in preclinical animal models. [1]

C25H21N2OF3

422.442

422.161

956274-94-5

17751090

White to off-white solid powder

6.646

2

5

4

31

627

0

CC(C)(C1=CC=CC=C1C2=CC3=C(C=C2)N=C(N3)/C=C/C4=CC=C(C=C4)C(F)(F)F)O

ORDHXXHTBUZRCN-NTEUORMPSA-N

InChI=1S/C25H21F3N2O/c1-24(2,31)20-6-4-3-5-19(20)17-10-13-21-22(15-17)30-23(29-21)14-9-16-7-11-18(12-8-16)25(26,27)28/h3-15,31H,1-2H3,(H,29,30)/b14-9+

(E)-2-(2-(2-(4-(trifluoromethyl)styryl)-1H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol

JNJ39439335; JNJ 39439335; JNJ-39439335

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~16.67 mg/mL (~39.46 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.92 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 25.0 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.

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Solubility in Formulation 2: 2.5 mg/mL (5.92 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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.

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 (Please use freshly prepared in vivo formulations for optimal results.)