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Purity: ≥98%
TR-14035 is a novel, dual antagonist of alpha4beta7 integrin with IC50 of 7 nM and alpha4beta1 integrin with IC50 of 87 nM. TR14035 blocked the binding of human alpha(4)beta(7) to an (125)I-MAdCAM-Ig fusion protein with IC(50) values of 2.93 and 0.75 nM, respectively. It inhibited binding of soluble ligands to alpha(4)beta(1) or alpha(4)beta(7) on cells of human or rodent origin with similar potency. Under shear flow in vitro. TR-14035 (IC(50) alpha(4)beta(7)/alpha(4)beta(1)=7/87 nM) has completed Phase I studies in Europe.
| Targets |
α4β7 (IC50=7 nM); α4β1 (IC50=87 nM)
Integrin α4β7/α4β1 (IC50 α4β7/α4β1 = 7/87 nM for TR-14035) [1] Integrin α4β7/α4β1 (IC50 for binding to ¹²⁵I-MAdCAM-Ig fusion protein = 0.75 nM for α4β7; IC50 for blocking α4β7-dependent adhesion of RPMI-8866 cells to MAdCAM-Ig under shear flow = 0.1 μM) [2] |
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| ln Vitro |
At 1 μM, TR14035 completely prevents RPMI-8866 cells from adhering to MAdCAM-Ig, with an IC50 of roughly 0.01 μM [2].
1. TR-14035 is a potent dual antagonist of α4β7/α4β1 integrins, optimized from an initial lead compound (IC50 α4β7/α4β1=5/33 μM) to low nanomolar potency; it is one of the orally bioavailable derivatives from N-benzoyl-L-biphenylalanine series [1] 2. TR-14035 blocks the binding of human α4β7 to soluble ¹²⁵I-MAdCAM-Ig fusion protein with an IC50 of 0.75 nM, and inhibits ligand binding to α4β1/α4β7 on human/rodent cells with similar potency [2] 3. Under in vitro shear flow conditions, TR-14035 blocks the adhesion of human α4β7-expressing RPMI-8866 cells or murine mesenteric lymph node lymphocytes to MAdCAM-Ig with an IC50 of 0.1 μM [2] 4. TR-14035 (in vitro) inhibits IL-4-induced leukocyte rolling flux (48% reduction), adhesion (100% reduction) and emigration (99% reduction) in rat mesenteric postcapillary venules, by targeting α4β1/α4β7 integrins [3] |
| ln Vivo |
In a rat model of allergic asthma, TR-14035 (3 mg/kg; ig) dramatically decreases airway hyperresponsiveness to serotonin (5-HT) [3]. Oral administration of TR-14035 is used (10 mg/kg in rats and 10 mg/kg in dogs) [4]. TR-14035 is caused by a high plasma clearance after intravenous injection (3 mg/kg in rats and 3 mg/kg in dogs) with values of 3865 and 1664 mL/h/kg, respectively [4].
1. In intravital microscopy studies of murine Peyer's patch HEVs, TR-14035 blocks α4β7-dependent adhesion of Mn²⁺-prestimulated fluorescent murine lymphocytes with an ED50 of 0.01-0.1 mg/kg (i.v.); anti-α4 mAb (10 mg/kg i.v.) blocks adhesion by 95%, while anti-β1 mAb has no effect [2] 2. In Brown Norway rats with allergic asthma (actively sensitized and aerosol antigen-challenged), oral administration of TR-14035 (3 mg/kg, given 1 h before and 4 h after antigen challenge) suppresses airway hyper-responsiveness to intravenous 5-hydroxytryptamine (reduced lung resistance and increased lung compliance at 24 h post-challenge, P<0.05 vs antigen-challenged controls) [3] 3. TR-14035 (3 mg/kg p.o.) reduces eosinophil, neutrophil, lymphocyte and macrophage counts in bronchoalveolar lavage fluid (BALF) of asthmatic rats at 24 and 48 h post-antigen challenge (total cell counts: 1.28±0.18×10⁶ cells/ml for control vs 0.42±0.10×10⁶ cells/ml for treated at 24 h, P<0.05) [3] 4. TR-14035 (3 mg/kg p.o.) decreases eosinophil peroxidase activity and protein content in BALF of asthmatic rats at 24 h post-challenge (P<0.05 vs controls) [3] 5. TR-14035 (3 mg/kg p.o.) suppresses antigen-induced lung IL-5 mRNA upregulation at 24 h post-challenge in asthmatic rats (P<0.05 vs controls), while IL-4 levels in BALF are not significantly affected [3] 6. Histological analysis shows TR-14035 (3 mg/kg p.o.) markedly reduces peribronchial, perivascular and alveolar inflammatory cell infiltration in the lungs of asthmatic rats at 24 and 48 h post-challenge [3] |
| Enzyme Assay |
TR-14035 is a novel, dual antagonist of alpha4beta7 integrin with IC50 of 7 nM and alpha4beta1 integrin with IC50 of 87 nM.
1. Integrin-ligand binding assay for α4β7: Human α4β7-expressing cells were incubated with TR-14035 at gradient concentrations, then co-incubated with ¹²⁵I-MAdCAM-Ig fusion protein; the bound radioactivity was measured to calculate IC50 values for TR-14035 inhibition of α4β7-MAdCAM binding [2] 2. Shear flow adhesion assay: RPMI-8866 cells (human α4β7⁺) or murine mesenteric lymph node lymphocytes were pretreated with TR-14035 at different concentrations, then perfused over MAdCAM-Ig-coated surfaces under controlled shear flow conditions; the number of adherent cells was counted to determine IC50 [2] |
| Cell Assay |
1. Integrin expression and binding assay: Human/rodent cells expressing α4β1/α4β7 were incubated with TR-14035 at gradient concentrations, then exposed to soluble α4 integrin ligands; ligand binding was quantified to evaluate the inhibitory potency of TR-14035 [2]
2. Leukocyte rolling/adhesion/emigration assay (in vitro): Rat mesenteric postcapillary venules were exposed to IL-4 (1 μg/rat) for 24 h, then treated with TR-14035; leukocyte rolling flux, rolling velocity, adhesion and emigration were quantified by microscopic observation [3] 3. BALF cell counting assay: Bronchoalveolar lavage fluid was collected from asthmatic rats treated with/without TR-14035; eosinophils, neutrophils, lymphocytes and macrophages were counted using standard cytological methods, and total cell counts were calculated [3] 4. Eosinophil peroxidase activity assay: BALF samples from asthmatic rats were processed to measure eosinophil peroxidase activity using a colorimetric method, to evaluate eosinophil infiltration [3] 5. IL-5 mRNA quantification assay: Lung tissue from asthmatic rats was collected, total RNA was extracted, and IL-5 mRNA levels were measured by real-time quantitative RT-PCR (ΔΔCt method, normalized to GAPDH) [3] 6. IL-4 enzyme-immunoassay: IL-4 concentrations in BALF from asthmatic rats were quantified using an enzyme-linked immunosorbent assay (ELISA) [3] |
| Animal Protocol |
Animal/Disease Models: Male Brown Norway rats (250-300 g)[3]
Doses: 3 mg/kg Route of Administration: po (oral gavage), 1 h before and 3 h after antigen challenge Experimental Results: Suppressed antigen-induced airway hyper-responsiveness and inflammation. Animal/Disease Models: Male SD (Sprague-Dawley) rats (250-320 g)[4] Doses: 3 mg/kg for iv; 10 mg/kg for oral (pharmacokinetic/PK Analysis) Route of Administration: intravenous (iv) injection and oral administration Experimental Results: Oral bioavailability (17.1%) , Cmax (0.18 μg eq./mL), T1/2 (0.28 h). Animal/Disease Models: Male beagle dogs[4] Doses: 3 mg/kg for iv; 10 mg/kg for oral (pharmacokinetic/PK Analysis) Route of Administration: intravenous (iv) administration and oral administration Experimental Results: Oral bioavailability (13.2%), Cmax (0.10 μg eq./mL), T1/2 (0.81 h). 1. Mouse Peyer's patch HEV adhesion model: Murine lymphocytes were prestimulated with 2 mM Mn²⁺ to activate α4β7; TR-14035 was administered intravenously at doses of 0.01-0.1 mg/kg (ED50 range), or anti-α4/anti-β1 mAbs were given (10 mg/kg i.v.); intravital microscopy was used to quantify lymphocyte adhesion to Peyer's patch HEVs [2] 2. Brown Norway rat allergic asthma model: Rats were actively sensitized, then challenged with aerosol antigen on day 21; TR-14035 was administered orally at 3 mg/kg (1 h before and 4 h after antigen challenge); airway hyper-responsiveness to 5-hydroxytryptamine was evaluated by measuring lung resistance (RL) and dynamic compliance (Cdyn) at 24 and 48 h post-challenge [3] 3. Rat mesenteric microcirculation model: Rats were injected intraperitoneally with 5 ml saline or 5 ml IL-4 (1 μg/rat); TR-14035 was given orally at 3 mg/kg (1 h before and 3 h after IL-4 injection); intravital microscopy was used to measure leukocyte rolling flux, adhesion and emigration in mesenteric postcapillary venules 24 h later [3] 4. Rat/dog pharmacokinetic study: TR-14035 was administered to Sprague-Dawley rats and dogs at 10 mg/kg (oral) or intravenous doses; plasma, bile, urine samples were collected at different time points to measure drug concentrations and metabolites [4] |
| ADME/Pharmacokinetics |
Metabolism / Metabolites
Known metabolites of (S)-2-(2,6-dichlorobenzoamide)-3-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)propionic acid include 2-[(2,6-dichlorobenzoyl)amino]-3-[4-(2-hydroxy-6-methoxyphenyl)phenyl]propionic acid. 1. Oral bioavailability: The oral bioavailability of TR-14035 is low, at 17% in rats and 13% in dogs (oral dose of 10 mg/kg)[4] 2. Absorption: In rats, at least 63% of the oral dose of TR-14035 is absorbed from the gastrointestinal tract[4] 3. Excretion: Approximately one-third of the intravenously administered TR-14035 is excreted unchanged in the bile in rats and dogs; urinary excretion is a secondary elimination route[4] 4. Metabolism: Species-dependent metabolism was observed; the major metabolite was O-demethyl TR-14035 (detected in rats, dogs and humans); O-demethyl TR-14035 is bound to sulfate in rats but not in dogs and humans[4] 5. Kidney processing: TR-14035 is reabsorbed in the proximal tubules of rat kidneys, while in dogs it is secreted into the renal tubules via an active transport system [4]. 6. Clearance: TR-14035 is widely cleared in rats and dogs, and oral bioavailability is limited by significant first-pass metabolism and bile excretion [4]. |
| References |
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| Additional Infomation |
1. TR-14035 (N-(2,6-dichlorobenzoyl)-4-(2',6'-bismethoxyphenyl)phenylalanine) is a novel N-benzoyl-L-biphenylalanine derivative and a second-generation dual α4β7/α4β1 integrin antagonist [1][2]. 2. α4β1/α4β7 integrins regulate the recruitment of leukocytes to sites of inflammation (e.g., α4β7 is recruited to the gastrointestinal tract via MAdCAM-1 and to the airways in asthma), making them key targets for the treatment of inflammatory/autoimmune diseases [1][2][3]. 3. TR-14035 has completed a Phase I clinical trial in Europe [1]. 4. TR-14035 has oral activity and inhibits airway leukocyte recruitment and hyperresponsiveness in an allergic asthma model, suggesting potential therapeutic value. Used for the treatment of asthma [3]
5. First-pass metabolism and bile excretion are the main factors limiting the oral bioavailability of TR-14035 [4] |
| Molecular Formula |
C24H21CL2NO5
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|---|---|---|
| Molecular Weight |
474.33
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| Exact Mass |
473.079
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| Elemental Analysis |
C, 60.77; H, 4.46; Cl, 14.95; N, 2.95; O, 16.86
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| CAS # |
232271-19-1
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| Related CAS # |
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| PubChem CID |
9912743
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
604.0±55.0 °C at 760 mmHg
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| Flash Point |
319.1±31.5 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.607
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| LogP |
3.67
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
32
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| Complexity |
606
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| Defined Atom Stereocenter Count |
1
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| SMILES |
ClC1C([H])=C([H])C([H])=C(C=1C(N([H])[C@]([H])(C(=O)O[H])C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])C1C(=C([H])C([H])=C([H])C=1OC([H])([H])[H])OC([H])([H])[H])=O)Cl
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| InChi Key |
DRSJLVGDSNWQBI-SFHVURJKSA-N
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| InChi Code |
InChI=1S/C24H21Cl2NO5/c1-31-19-7-4-8-20(32-2)21(19)15-11-9-14(10-12-15)13-18(24(29)30)27-23(28)22-16(25)5-3-6-17(22)26/h3-12,18H,13H2,1-2H3,(H,27,28)(H,29,30)/t18-/m0/s1
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| Chemical Name |
N-(2,6-Dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~95 mg/mL ( 200.28 mM）
Water: <20 mg/mL Ethanol: Insoluble |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.27 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.27 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 25.0 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 | 2.1082 mL | 10.5412 mL | 21.0824 mL | |
| 5 mM | 0.4216 mL | 2.1082 mL | 4.2165 mL | |
| 10 mM | 0.2108 mL | 1.0541 mL | 2.1082 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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