| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| Other Sizes |
Purity: ≥98%
BAY-1316957 (BAY1316957) is a novel, highly potent, selective, and orally bioavailable antagonist of human prostaglandin E2 receptor subtype 4 (hEP4 receptor) with the potential to be used for the Treatment of Endometriosis. It inhibits hEP4-R with an IC50 of 15.3 nM. The presence and growth of endometrial tissue outside the uterine cavity in endometriosis patients are primarily driven by hormone-dependent and inflammatory processes-the latter being frequently associated with severe, acute, and chronic pelvic pain. The EP4 subtype of prostaglandin E2 (PGE2) receptors (EP4-R) is a particularly promising anti-inflammatory and antinociceptive target as both this receptor subtype and the pathways forming PGE2 are highly expressed in endometriotic lesions. High-throughput screening resulted in the identification of benzimidazole derivatives as novel hEP4-R antagonists. Careful structure-activity relationship investigation guided by rational design identified a methyl substitution adjacent to the carboxylic acid as an appropriate means to accomplish favorable pharmacokinetic properties by reduction of glucuronidation. Further optimization led to the identification of benzimidazolecarboxylic acid BAY 1316957, a highly potent, specific, and selective hEP4-R antagonist with excellent drug metabolism and pharmacokinetics properties. Notably, treatment with BAY 1316957 can be expected to lead to prominent and rapid pain relief and significant improvement of the patient's quality of life.
| Targets |
Caco-2 cells demonstrate the excellent solubility and permeability of BAY-1316957 (Compound 32) [1].
|
|---|---|
| ln Vitro |
Caco-2 cells demonstrate the excellent solubility and permeability of BAY-1316957 (Compound 32) [1].
BAY-1316957 is a highly potent and selective full antagonist of the human EP4 receptor, with an IC₅₀ of 15.3 ± 10.7 nM in a cell-based functional cAMP assay. It maintains excellent selectivity over human EP2 and DP1 receptors, with no significant antagonistic activity detected against these receptors. The compound also shows favorable potency across species (rat, mouse, cynomolgus monkey) based on earlier lead optimization data. [1] Metabolic stability studies in human, rat, mouse, dog, and monkey hepatocytes indicate that the primary biotransformation pathway is direct glucuronidation of the carboxylic acid moiety, mainly catalyzed by UGT1A1 and to a lesser extent UGT1A3. [1] |
| ln Vivo |
In the dmPGE2 pain model, treatment with BAY-1316957 (Compound 32; 0.2–5 mg/kg; oral; once) dramatically decreased mechanical allodynia [1]. In Wistar rats, the pharmacokinetic characteristics of BAY-1316957 (Compound 32) demonstrated a lengthy half-life, low clearance, and high bioavailability (F%=90%). Research on the metabolism of BAY-1316957 (compound 32) in hepatocytes from humans, rats, mice, dogs, and monkeys revealed that the production of acyl glucuronides is another frequent and important pathway for biotransformation, mostly catalyzed and transformed by UGT1A1 to a lesser extent by UGT1A3 [1].
Oral administration of BAY-1316957 (5 mg/kg) significantly reduced mechanical allodynia in a rat model of dmPGE2-induced inflammatory pain, as measured by increased paw withdrawal thresholds compared to vehicle-treated controls. This demonstrates its potent anti-nociceptive and anti-inflammatory activity in vivo. [1] |
| Enzyme Assay |
A cell-based functional assay measuring antagonism of human EP4 receptor activity was used. Frozen cells expressing the receptor were incubated with test compounds and stimulated with PGE2 agonist. Agonist-induced cAMP production was measured using a non-radioactive HTRF assay based on competition between endogenous cAMP and a fluorescently labeled cAMP-d2 donor for binding to a Europium cryptate-labeled anti-cAMP antibody. The assay was performed in 384-well or 1536-well formats, and IC₅₀ values were determined by 4-parameter fitting. [1]
Similar assay formats were used for species-specific EP4 receptor activity (rat, mouse, cynomolgus monkey) and for selectivity screening against human EP2 and DP1 receptors. [1] |
| Cell Assay |
The same cell-based cAMP HTRF assay was used for all receptor activity and selectivity profiling. Cells were thawed, resuspended in appropriate medium, seeded into assay plates, and preincubated with test compounds before agonist addition. After incubation, cells were lysed, and cAMP levels were detected via HTRF readout. Data were analyzed using commercial or in-house software for IC₅₀ calculation. [1]
Caco-2 permeability assays were conducted to evaluate absorption potential. Cells were grown on inserts for 15 days, and test compounds were added to either apical or basolateral compartments. Permeability (Papp) and efflux ratios were calculated after 2-hour incubation. [1] |
| Animal Protocol |
Animal/Disease Models: Male adult Sprague Dawley rats (220-265 g) were injected with 16,16-dimethyl prostaglandin E2 (dmPGE2) [1]
Doses: 0.2 mg/kg, 1 mg/kg, 5 mg/kg Route of Administration: oral administration; injection administration; injection administration. Experimental Results: Paw withdrawal threshold was Dramatically diminished in the dmPGE2 pain model. For pharmacokinetic studies in rats, BAY-1316957 was administered intravenously (0.3–1 mg/kg) or orally (0.5–10 mg/kg) formulated in PEG400-containing solutions. Blood samples were collected at multiple time points, plasma was separated, and compound concentration was determined by LC-MS/MS. PK parameters were calculated using non-compartmental analysis. [1] For the dmPGE2-induced pain model, male Sprague-Dawley rats were orally administered BAY-1316957 (0.2, 1.0, or 5.0 mg/kg) suspended in 0.5% carboxymethylcellulose (CMC) solution, 60 minutes before intraplantar injection of dmPGE2 (10 µg) into the hind paw. Mechanical allodynia was assessed using an electronic von Frey apparatus, measuring paw withdrawal thresholds before and after treatment. [1] |
| ADME/Pharmacokinetics |
BAY-1316957 has a low blood clearance rate (rat CLblood = 0.43 L/h/kg), a long half-life (rat t₁/₂ = 24 h after oral administration), high oral bioavailability (rat F = 90%), and low to moderate plasma protein binding (free fraction not determined, but inferred from stability studies). [1]
Its main elimination pathway is through direct glucuronidation via UGT1A1/1A3 to form acyl glucuronide metabolites, which are excreted via bile and partially cleaved back into the parent compound in feces. [1] High Caco-2 cell permeability (Papp AB = 205.9 nm/s) and low efflux ratio (0.6) indicate good absorption potential. [1] |
| References | |
| Additional Infomation |
BAY-1316957 is a benzimidazole carboxylic acid derivative developed as a potent and selective EP4 receptor antagonist for the treatment of inflammatory pain associated with endometriosis. [1]
It is designed with a methyl group introduced at the ortho position of the carboxylic acid group to reduce glucuronidation and improve metabolic stability. [1] Due to its favorable pharmacokinetic properties, this compound is intended for once-daily oral administration in humans. [1] |
| Molecular Formula |
C27H27N3O3
|
|---|---|
| Molecular Weight |
441.5216
|
| Exact Mass |
441.205
|
| CAS # |
1613264-40-6
|
| PubChem CID |
90202558
|
| Appearance |
White to off-white solid powder
|
| LogP |
4.9
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
33
|
| Complexity |
704
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
O(C)CCN1C2C=CC(C(=O)O)=C(C)C=2N=C1C1C=CC2=C(C=1)C1C=C(C)C=CC=1N2CC
|
| InChi Key |
FHXIZAPGGULPIK-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C27H27N3O3/c1-5-29-22-9-6-16(2)14-20(22)21-15-18(7-10-23(21)29)26-28-25-17(3)19(27(31)32)8-11-24(25)30(26)12-13-33-4/h6-11,14-15H,5,12-13H2,1-4H3,(H,31,32)
|
| Chemical Name |
2-(9-Ethyl-6-methyl-9H-carbazol-3-yl)-1-(2-methoxyethyl)-4-methyl-1H-benzimidazole-5-carboxylic acid
|
| Synonyms |
BAY1316957; BAY 1316957; BAY-1316957
|
| 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)
|
| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~226.49 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (11.32 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 50.0 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.71 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 20.8 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2649 mL | 11.3245 mL | 22.6490 mL | |
| 5 mM | 0.4530 mL | 2.2649 mL | 4.5298 mL | |
| 10 mM | 0.2265 mL | 1.1325 mL | 2.2649 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.
 |
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA