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Purity: ≥98%
TAK-715 is a novel, potent and selective p38 MAPK (p38 mitogen-activated protein) inhibitor with potential anti-inflammatory activity. It has an IC50 of 7.1 nM, is 28-fold more selective for p38 than p38, and exhibits little to no inhibition of JNK1, ERK1, IKK, MEKK1, or TAK1. It also shows little to no inhibition of p38γ/δ, and inhibits p38α only. For the treatment of Rheumatoid arthritis-RA, TAK-715 is currently being studied in clinical trials.
| Targets |
p38α (IC50 = 7.1 nM); p38β (IC50 = 200 nM); p38δ (IC50 >10 μM); p38γ (IC50 >10 μM); CK1δ; CK1ε
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| ln Vitro |
TAK 715 has an IC50 of 48 nM and inhibits LPS-stimulated TNF-alpha release from THP-1. [1] Wnt-3a-induced hDvl2 phosphorylation and the hDvl2 shift in U2OS-EFC cells are inhibited by TAK 715 (10 μM).[2] The main-chain carbonyl of Met109 of p38 alpha is hydrogen bonded to the amide NH of TAK 715. TAK 715 occupies the hydrophobic back pocket, the adenine region, the front pocket of p38, as well as the majority of the length of the Gly-rich loop, and binds relatively high in the ATP pocket.[3]
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| ln Vivo |
TAK 715 (10 mg/kg, po) reduces the amount of TNF-alpha produced by LPS in mice by 87.6%. TAK 715 has a modest bioavailability in mice of 18.4% and a marginally better bioavailability in rats of 21.1%. TAK 715 has a modest bioavailability in mice of 18.4% and a marginally better bioavailability in rats of 21.1%. Rats treated with TAK 715 have a Cmax of 0.19 μg/mL and an AUC(0-24 hours) of 1.16 μg/h/mL. In a rat adjuvant-induced arthritis (AA) model, TAK 715 (30 mg/kg, po) significantly lowers the secondary paw volume with 25% inhibition. [1]
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| Enzyme Assay |
TAK-715 is a p38α MAPK inhibitor with an IC50 of 7.1 nM that is 28-fold more selective for p38α over p38β, with no inhibition to p38γ/δ, JNK1, ERK1, IKKβ, MEKK1 or TAK1.
Biological Methods. [1] p38 MAP Kinase Assay, THP-1 TNF-α Release Assay and Mouse TNF-α Release Assay. These assays were performed according to the protocols described previously [Chem. Pharm. Bull.2005, 53, 410−418]. Measurement of CYP Inhibition Activity. [1] The inhibition activity of the thiazole derivatives on CYP3A4 was evaluated by incubating 40 μM 7-benzyloxyquinoline with the microsomes derived from CYP3A4-expressing insect cell in the presence of 1 μM compounds. The concentration of 7-benzyloxyquinoline metabolite was measured with a spectrofluorometer. The inhibition activity of compound 8h (TAK-715) on CYP isoforms was also evaluated by using specific CYP-expressing human B-limphoblastoid cells. The concentrations of 8h (TAK-715) were 1, 10, and 100 μM. The substrates of each CYPs were 4 μM ethoxyresorufin for CYP1A1 and CYP1A2, 400 μM coumarin for CYP2A6, 400 μM 7-ethoxycoumarin for CYP2B6, 400 μM tolbutamide for CYP2C8 and CYP2C9, 80 μM S-(±)-mephenytoin for CYP2C19, 200 μM (±)-bufuralol for CYP2D6, 500 μM 4-nitrophenol for CYP2E1, and 80 μM testosterone for CYP3A4. The concentration of the marker metabolite for CYP1A1, CYP1A2, and CYP2A6 was measured with a spectrofluorometer, and for the other CYPs it was measured by HPLC. |
| Cell Assay |
TAK 715 has an IC50 of 48 nM and inhibits LPS-stimulated TNF-alpha release from THP-1. In U2OS-EFC cells, TAK 715 (10 μM) prevents Wnt-3a-induced hDvl2 phosphorylation and the hDvl2 shift. The main-chain carbonyl of Met109 of p38 alpha is hydrogen bonded to the amide NH of TAK 715. TAK 715 occupies the hydrophobic back pocket, the adenine region, the front pocket of p38, as well as the majority of the length of the Gly-rich loop, and binds relatively high in the ATP pocket.
Researchers subsequently tested the ability of the four p38 inhibitors to inhibit the Wnt-3a-induced hDvl2 mobility shift in U2OS-EFC cells. TAK-715 and AMG-548 inhibited the hDvl2 shift at 10 μM, whereas Scio-469 and VX-745 did not (Figure 5A). Upon Wnt treatment, Ser1490 of LRP6 is phosphorylated by the sequential activity of GSK3 and CKIγ (Tamai et al., 2004, Davidson et al., 2005). We did not observe any change in LRP6 phosphorylation by TAK-715 or AMG-548 (Figure 5A), indicating that inhibition of CKIγ did not contribute to the inhibitory effect of these compounds on Wnt/β-catenin signaling. This is consistent with the inability of both compounds to inhibit CKIγ in biochemical assays (Figures 3A and 3B). We subsequently studied the dose-dependency of the TAK-715- and AMG-548-mediated inhibition of Wnt-3a-induced hDvl2 phosphorylation. TAK-715 and AMG-548 inhibited the hDvl2 shift at micromolar concentrations (Figure 5B). In contrast, Scio-469 and VX-745 did not inhibit the Wnt-3a-induced hDvl2 mobility shift at concentrations up to 10 μM (Figure 5C). The peak intensity ratio of nonphosphorylated versus phosphorylated hDvl2 of these blots is depicted in Figure S6. Thus, the concentrations of TAK-715 and AMG-548 necessary to inhibit CKIδ/ɛ in cells closely approximate those required to inhibit Wnt/β-catenin signaling in the TOPflash and EFC assays. This finding, along with the biochemical profile of TAK-715 and AMG-548, strongly suggests that the effect of these compounds on Wnt/β-catenin signaling is mediated through CKIδ/ɛ cross-reactivity.[2] |
| Animal Protocol |
Adjuvant-induced arthritis (AA) rat model
30 mg/kg Orally administered Adjuvant-Induced Arthritis Assay. Arthritis was induced in 7-week-old male Lewis rats (n = 6) by an intradermal injection of 0.25 mg of Mycobacterium tuberculosis in 0.05 mL of liquid paraffin at a site on the right hind paw on day 0. The paw volume of the untreated (left) hind paw was determined on day 14. Drugs (3, 10, and 30 mg/kg, po) and the vehicle (saline) were administered from day 0 to day 13.[1] |
| References | |
| Additional Infomation |
N-[4-[2-ethyl-4-(3-methylphenyl)-5-thiazolyl]-2-pyridinyl]benzamide is a member of benzamides.
TAK-715 is under investigation in clinical trial NCT00760864 (Safety and Efficacy of TAK-715 in Subjects With Rheumatoid Arthritis). |
| Molecular Formula |
C24H21N3OS
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| Molecular Weight |
399.51
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| Exact Mass |
399.14
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| Elemental Analysis |
C, 72.15; H, 5.30; N, 10.52; O, 4.00; S, 8.03
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| CAS # |
303162-79-0
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| Related CAS # |
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| PubChem CID |
9952773
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| Appearance |
Light to dark yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
495.3±45.0 °C at 760 mmHg
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| Flash Point |
253.3±28.7 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.656
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| LogP |
4.38
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
29
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| Complexity |
538
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1=CC=CC=C1)NC2=NC=CC(C3=C(N=C(S3)CC)C4=CC=CC(C)=C4)=C2
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| InChi Key |
HEKAIDKUDLCBRU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H21N3OS/c1-3-21-27-22(18-11-7-8-16(2)14-18)23(29-21)19-12-13-25-20(15-19)26-24(28)17-9-5-4-6-10-17/h4-15H,3H2,1-2H3,(H,25,26,28)
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| Chemical Name |
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]pyridin-2-yl]benzamide
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| Synonyms |
TAK 715; TAK715; 303162-79-0; N-(4-(2-ethyl-4-(m-tolyl)thiazol-5-yl)pyridin-2-yl)benzamide; TAK715; UNII-WE92U03C5Z; Benzamide, N-[4-[2-ethyl-4-(3-methylphenyl)-5-thiazolyl]-2-pyridinyl]-; WE92U03C5Z; TAK-715
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.26 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 (6.26 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. View More
Solubility in Formulation 3: 30% propylene glycol, 5% Tween 80, 65% D5W: 30mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5031 mL | 12.5153 mL | 25.0307 mL | |
| 5 mM | 0.5006 mL | 2.5031 mL | 5.0061 mL | |
| 10 mM | 0.2503 mL | 1.2515 mL | 2.5031 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00760864 | Completed | Drug: TAK-715 and methotrexate Drug: Methotrexate |
Arthritis, Rheumatoid | Takeda | August 2004 | Phase 2 |
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