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| Targets |
LPA1 Receptor 1.7-14.5 nM (Kd)
KISS1 receptor (KISS1R). TAK-683 acetate is a potent KISS1R agonist, with an IC50 of 170 pM in receptor binding assays. It has an EC50 of 0.96 nM for the human KISS1R and an EC50 of 1.6 nM for the rat KISS1R. The compound indirectly targets the GnRH system by binding to and activating hypothalamic KISS1R, which in turn stimulates the release of gonadotropin-releasing hormone (GnRH). TAK-615 specifically targets the LPA1 receptor (lysophosphatidic acid receptor 1), a G protein-coupled receptor that plays a significant role in the initiation and progression of pulmonary fibrosis. It functions as a negative allosteric modulator (NAM), meaning it binds to a site distinct from the orthosteric binding site to inhibit receptor function. TAK-615 binds to the LPA1 receptor with high affinity, exhibiting a Kd of 1.7 ± 0.5 nM for the high-affinity site and 14.5 ± 12.1 nM for the low-affinity site. |
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| ln Vitro |
TAK-615 has a specific binding affinity of 1.7±0.5 nM for human LPA1 receptor-expressing membranes and 14.5±12.1 nM for Kd low affinity (KdLo) receptors[1]. Only about 40% of the LPA response can be inhibited by TAK-615 at 10 µM, with an IC50 of 23±13 nM in the β-arrestin assay, and 60% at 10 µM, with an IC50 of 91±30 nM in the calcium mobilization assay [1].
TAK-683 acetate acts as a potent full agonist of the KISS1 receptor (KISS1R), with an IC50 of 170 pM. In Ca2+ mobilization assays using rat KISS1R-expressing CHO cells, it shows an EC50 of 180 pM. The compound has improved metabolic stability compared to natural metastin. It indirectly affects GnRH neurons by stimulating KISS1R, leading to a transient increase in luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. In vitro, TAK-615 specifically binds to membranes expressing the human LPA1 receptor with high affinity. Its activity is characterized by its negative allosteric modulation, which inhibits LPA1-mediated signaling pathways. The compound's high-affinity binding (Kd of 1.7 nM) demonstrates its potent interaction with the target receptor, making it a valuable tool for studying LPA1 function in cellular models of fibrosis and inflammation. |
| ln Vivo |
TAK-683 acetate effectively depletes GnRH in the hypothalamus and reduces plasma levels of FSH, LH, and testosterone in vivo. Following repeated subcutaneous administration, plasma hormone levels and genital organ weights are reduced. In a rat prostate cancer model, it suppresses serum PSA to below detection limits. TAK-683 provides a promising approach for treating hormone-related diseases, and TAK-683 was evaluated in Phase 1 clinical trials for prostate cancer.
In vivo activity data for TAK-615 are primarily related to its research application in pulmonary fibrosis. As a negative allosteric modulator of LPA1, the compound is expected to attenuate LPA1-mediated fibrotic and inflammatory responses in animal models. Studies typically involve administration to rodent models of pulmonary fibrosis to assess its efficacy in reducing fibrosis, inflammation, and other disease-related endpoints. |
| Enzyme Assay |
Receptor binding assays are performed using membranes from rat KISS1R-expressing Chinese hamster ovary (CHO) cells. The membranes are incubated with a radiolabeled ligand (e.g., 125I-kisspeptin) and increasing concentrations of unlabeled TAK-683 acetate (0-1000 nM) for 60-90 min at room temperature. Non-specific binding is determined with excess unlabeled metastin. Bound radioactivity is separated by filtration, and the IC50 is calculated via non-linear regression. The 95% confidence interval is reported as 150-180 pM.
For non-cellular in vitro binding assays, TAK-615 is evaluated for its affinity to the LPA1 receptor using membrane preparations expressing the human LPA1 receptor. The compound is incubated with the membrane preparations, and binding affinity is measured using radioligand binding or other biophysical techniques. The dissociation constant (Kd) is determined, with values of 1.7 nM for the high-affinity site and 14.5 nM for the low-affinity site. |
| Cell Assay |
A functional Ca2+ mobilization assay can be performed using the same rat KISS1R-expressing CHO cells. Cells are loaded with a fluorescent Ca2+-sensitive dye (e.g., Fluo-4 AM). Increasing concentrations of TAK-683 acetate (0-1000 nM) are added, and the change in fluorescence intensity is measured using a fluorescence plate reader. The EC50 is calculated from the dose-response curve, with a reported value of 180 pM (159-203 pM 95% CI).
For in vitro cellular assays, TAK-615 is tested in cell lines expressing the LPA1 receptor to assess its effects on LPA1-mediated signaling. Cells are treated with the compound, and downstream signaling pathways (such as calcium mobilization, ERK phosphorylation, or other G protein-coupled receptor readouts) are measured. The compound's negative allosteric modulation is confirmed by its ability to inhibit LPA-induced signaling without competing with the orthosteric ligand. |
| Animal Protocol |
In a pharmacokinetic and efficacy study, male rats with an androgen-dependent prostate cancer model received TAK-683 acetate via subcutaneous osmotic minipumps for up to 12 weeks. The doses ranged from 2.1 to 21 nmol/kg/day. Serum concentrations of PSA were monitored as a pharmacodynamic biomarker. By day 14, PSA levels were reduced to below the limit of detection (0.5 ng/ml) in all rats, demonstrating robust antitumor activity. Details on this model are published in a 2018 paper in the European Journal of Pharmacology by Tanaka et al..
For in vivo animal studies, TAK-615 is evaluated in mouse or rat models of pulmonary fibrosis. Fibrosis is typically induced by intratracheal administration of bleomycin or other fibrotic agents. Animals are treated with TAK-615 via oral or intraperitoneal administration at various doses. Efficacy is assessed by measuring lung fibrosis severity (using histopathological scoring, hydroxyproline content, or collagen deposition), inflammatory cell infiltration, and other disease-related biomarkers. |
| ADME/Pharmacokinetics |
TAK-683 acetate is a synthetic peptide with a molecular weight of 1358.5. It is typically administered via subcutaneous injection to ensure systemic bioavailability, as it has limited oral bioavailability. A one-month depot formulation of TAK-683 has been developed and evaluated for sustained activity. In preclinical studies, it exhibits a long half-life and a duration of action suitable for once-monthly dosing. The acetate salt enhances its aqueous solubility compared to the free base.
Pharmacokinetic data for TAK-615 are not extensively documented. As a small-molecule negative allosteric modulator with a molecular weight of 419.44, it is expected to have favorable oral bioavailability and tissue distribution. The compound is soluble in DMSO and can be formulated for in vivo administration. Further pharmacokinetic studies would be needed to fully characterize its absorption, distribution, metabolism, and excretion profile. |
| Toxicity/Toxicokinetics |
In preclinical studies with one-month depot formulations in male rats, TAK-683 acetate was well tolerated at doses that achieved sustained testosterone suppression. The primary toxicity profile is expected to be consistent with that of other agents that suppress sex hormone levels, which can lead to hot flashes, loss of libido, and potential effects on bone mineral density with long-term use. No specific toxicology data is published for the compound alone; it is for research use only.
Toxicological data for TAK-615 are limited. As a compound targeting the LPA1 receptor, its toxicity profile would be influenced by the physiological roles of LPA1 in various tissues. Comprehensive toxicology studies including acute and repeat-dose toxicity, genotoxicity, and organ-specific toxicity assessments would be required for therapeutic development. The compound is for research use only and not for human use. |
| References | |
| Additional Infomation |
TAK-683 acetate is an investigational metastin analog (KISS1R agonist) developed by Takeda. Its development was discontinued, reportedly after Phase 1 clinical trials in healthy men and patients with prostate cancer. It is an important research tool for studying the HPG axis, reproductive function, and hormone-sensitive cancers. TAK-683 acetate is not an approved drug and is for research use only.
TAK-615 is a negative allosteric modulator (NAM) of the LPA1 receptor being researched for pulmonary fibrosis. Its mechanism involves allosteric inhibition of LPA1, which is a key mediator of fibrotic and inflammatory responses. The compound has a molecular formula of C₂₅H₂₂FNO₄ and a molecular weight of 419.44. It is a valuable tool for studying the role of LPA1 signaling in fibrotic diseases and for validating LPA1 as a therapeutic target. |
| Molecular Formula |
C25H22FNO4
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|---|---|
| Molecular Weight |
419.444890499115
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| Exact Mass |
419.153
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| CAS # |
1664335-55-0
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| PubChem CID |
90659729
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| Appearance |
White to off-white solid powder
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| LogP |
4.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
31
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| Complexity |
609
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C=CC=CC=1OC1C=CC(=CC=1)C(N(CC1C=CC(C(=O)O)=CC=1)CC1CC1)=O
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| InChi Key |
LEZVXIZCJXKBJY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H22FNO4/c26-22-3-1-2-4-23(22)31-21-13-11-19(12-14-21)24(28)27(15-17-5-6-17)16-18-7-9-20(10-8-18)25(29)30/h1-4,7-14,17H,5-6,15-16H2,(H,29,30)
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| Chemical Name |
4-[[cyclopropylmethyl-[4-(2-fluorophenoxy)benzoyl]amino]methyl]benzoic acid
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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 |
| 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: 125 mg/mL (298.02 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.96 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 20.8 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 2: ≥ 2.08 mg/mL (4.96 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 20.8 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 | 2.3841 mL | 11.9207 mL | 23.8413 mL | |
| 5 mM | 0.4768 mL | 2.3841 mL | 4.7683 mL | |
| 10 mM | 0.2384 mL | 1.1921 mL | 2.3841 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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