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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.
| ln Vitro |
Caco-2 cells demonstrate the excellent solubility and permeability of BAY-1316957 (Compound 32) [1].
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| 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].
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| 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. |
| References |
[1]. Bäurle S, et al. Identification of a Benzimidazolecarboxylic Acid Derivative (BAY 1316957) as a Potent and Selective Human Prostaglandin E2 Receptor Subtype 4 (hEP4-R) Antagonist for the Treatment of Endometriosis. J Med Chem. 2019 Mar 14;62(5):2541-2563.
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| Molecular Formula |
C27H27N3O3
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|---|---|
| Molecular Weight |
441.5216
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| CAS # |
1613264-40-6
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| SMILES |
O=C(C1=CC=C2C(N=C(C3=CC4=C(C=C3)N(CC)C5=C4C=C(C)C=C5)N2CCOC)=C1C)O
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| InChi Key |
FHXIZAPGGULPIK-UHFFFAOYSA-N
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| 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)
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| Chemical Name |
2-(9-Ethyl-6-methyl-9H-carbazol-3-yl)-1-(2-methoxyethyl)-4-methyl-1H-benzimidazole-5-carboxylic acid
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| Synonyms |
BAY1316957; BAY 1316957; BAY-1316957
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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 : ~100 mg/mL (~226.49 mM)
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| 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.
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