In vitro activity: MK-2894 exhibits inhibitory effects on PGE2-induced cAMP accumulation and the EP4 functional potency in HEK 293 and HWB cells with IC50 values of 2.5 nM and 11 nM, respectively[1].

In vitro activity: MK-2894 exhibits inhibitory effects on PGE2-induced cAMP accumulation and the EP4 functional potency in HEK 293 and HWB cells with IC50 values of 2.5 nM and 11 nM, respectively[1].

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MK-2894 exhibits high binding affinity for human EP₄ receptor with Ki = 0.56 nM and functional IC₅₀ = 2.5 nM in a cAMP accumulation assay.
Binding affinity is not significantly shifted in the presence of 10% human serum (Ki = 0.97 nM).
In human whole blood assay, it blocks TNFα-induced IP-10 release with IC₅₀ = 11 ± 9 nM.
It behaves as a full antagonist in EP₄ functional assay with no agonist activity. [1]

MK-2894 (oral administration: 20 mg/kg; intravenous injection: 5 mg/kg) has a good pharmacokinetic profile in mice, with a moderate bioavailability of F=21% and a slow to moderate clearance rate of CL=23 mL/min/kg. It also has a good elimination half-life of T_1/2=15 h, a volume of distribution of 7.6 L/kg, and a maximum concentration reached in mice of C_max=1.4 μM.
MK-2894, administered orally at a dose of 20 mg/kg or intravenously at a dose of 5 mg/kg, demonstrates a good pharmacokinetic profile in SD-rats, a moderate bioavailability of 29%, and a slow to moderate clearance rate of 9.2 mL/min/kg. It also has a volume of distribution of 2.6 L/kg, good elimination half-lives of T_1/2=4.5 h, and a maximum concentration reached in mice of 4.5 μM[1].
MK-2894 (oral administration, 5 mg/kg; intravenous injection, 1 mg/kg) shows a good pharmacokinetic profile in dogs, with a moderate bioavailability of F=32% and a slow to moderate clearance rate of CL=23 mL/min/kg. In mice, the maximum concentration reached is C_max=3.3 μM, and the volume of distribution is V_dss=0.91 L/kg.[1]
MK-2894 (oral administration; 0.1 mg/kg–10 mg/kg; single dose) exhibits a dose-dependent inhibition of the acute carrageenan-induced mechanical hyperalgesia model in SD rats. It also shows an inhibition of pain response when measured three hours after the carrageenan injection subplantarly[1].
MK-2894 (oral administration; 0.1 mg/kg-10 mg/kg; 5 days) demonstrates strong activity in inhibiting chronic paw swelling in both the primary and secondary paws in a dose-dependent manner, the ED₅₀ value is 0.02 mg/kg/day. In an adjuvant-induced arthritis rat model, 24-hours after the last dose, the plasma concentration of 0.1 mg/kg/day is the point at which the secondary paw swelling is completely inhibited[1].

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In rat carrageenan-induced mechanical hyperalgesia model, oral administration of MK-2894 produced dose-dependent inhibition of pain response with ED₅₀ = 0.36 mg/kg and EC₅₀ = 250 nM.
In rat adjuvant-induced arthritis (AIA) model, it inhibited chronic paw swelling in both primary and secondary paws with ED₅₀ = 0.02 mg/kg/day and EC₅₀ ≈ 1 nM at 24 h after last dose.
Complete inhibition of secondary paw swelling was achieved at ED₁₀₀ = 0.1 mg/kg/day.
It showed superior potency compared to COX-2 inhibitors rofecoxib and MF-tricyclic in the same model. [1]

Radioligand binding assays were performed using membranes from HEK 293(EBNA) cells overexpressing human prostanoid receptors (EP₁₋₄, DP₁₋₂, TP, FP, IP).
Binding assays used respective ³H-prostaglandins or thromboxane as radioligands.
Assays were conducted in the absence or presence of 10% human serum to assess protein binding effects. [1]

EP₄ functional assay was performed in HEK 293 cells overexpressing human EP₄ receptor.
cAMP accumulation was induced by PGE₂ and measured to determine agonist/antagonist activity.
Human whole blood assay: blockade of TNFα-induced IP-10 release by EP₄ agonist L-902688 was measured. [1]

Rat carrageenan-induced hyperalgesia model: carrageenan was injected subplantarly, and compounds were administered orally 1 h later; pain response was measured at 3 h post-carrageenan.
Rat adjuvant-induced arthritis model: CFA was injected into primary paw on day 0; compounds were administered orally once daily from day 9 to day 17; paw swelling was measured.
GI tolerability model in rats: compounds were dosed orally for 5 days; on day 4, ⁵¹Cr-EDTA was administered orally and urinary ⁵¹Cr excretion was measured to assess GI mucosal permeability. [1]

MK-2894 showed moderate bioavailability in preclinical animal models: mice (F = 21%), rats (F = 29%), dogs (F = 32%), and cynomolgus monkeys (F = 18%). Plasma half-life: mice (15 hours), rats (4.5 hours), dogs (8.8 hours), and monkeys (19 hours). Clearance: mice (23 mL/min/kg), rats (9.2 mL/min/kg), dogs (3.2 mL/min/kg), and monkeys (0.91 mL/min/kg). Volume of distribution (Vss): mice (7.6 L/kg), rats (2.6 L/kg), dogs (0.91 L/kg), and monkeys (7.9 L/kg). [1]

In a rat model of gastrointestinal mucosal permeability, MK-2894 (3, 10, and 30 mg/kg/day for 5 consecutive days) did not cause significant ⁵¹Cr leakage, indicating good gastrointestinal tolerance. Conversely, indomethacin (5 mg/kg/day for 3 consecutive days) resulted in a significant increase in urinary ⁵¹Cr excretion. No significant covalent protein binding or formation of active metabolites was observed in human or rat liver microsomes. [1]

[1]. The discovery of 4-{1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]cyclopropyl}benzoic acid (MK-2894), a potent and selective prostaglandin E2 subtype 4 receptor antagonist. J Med Chem. 2010 Mar 11;53(5):2227-38.

[2]. Structural features of subtype-selective EP receptor modulators. Drug Discov Today. 2017 Jan;22(1):57-71.

MK-2894 is a second-generation EP₄ receptor antagonist developed to avoid the hydrolysis of acylsulfonamides, a common component of first-generation compounds, which produces metabolites with CYP 3A4 inhibition/induction potential. It is considered a safer alternative to nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors for the treatment of inflammatory pain and arthritis, with reduced gastrointestinal and cardiovascular side effects. EP₄ receptor antagonism has also been associated with atherosclerosis, cancer metastasis, migraines, and Alzheimer's disease. [1]

C25H22NO3F3S

473.50728

473.127

C, 63.41; H, 4.68; F, 12.04; N, 2.96; O, 10.14; S, 6.77

1006036-87-8

MK-2894 sodium salt; 1006036-88-9; 1006036-87-8 (free acid)

24952929

White to light brown solid powder

6.666

2

7

6

33

725

0

O=C(O)C1=CC=C(C2(NC(C3=C(C)SC(C)=C3CC4=CC=C(C(F)(F)F)C=C4)=O)CC2)C=C1

QJZQFVRFJCGDKF-UHFFFAOYSA-N

InChI=1S/C25H22F3NO3S/c1-14-20(13-16-3-7-19(8-4-16)25(26,27)28)21(15(2)33-14)22(30)29-24(11-12-24)18-9-5-17(6-10-18)23(31)32/h3-10H,11-13H2,1-2H3,(H,29,30)(H,31,32)

4-[1-[[2,5-dimethyl-4-[[4-(trifluoromethyl)phenyl]methyl]thiophene-3-carbonyl]amino]cyclopropyl]benzoic acid

MK 2894; MK-2894; MK2894

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ≥ 50 mg/mL (~105.6 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.28 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.

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Solubility in Formulation 2: 2.5 mg/mL (5.28 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
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 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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.28 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.

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 (Please use freshly prepared in vivo formulations for optimal results.)