p38α MAPK

BMS-751324 is featured with a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities. BMS-751324 was not only stable but also water-soluble under both acidic and neutral conditions.
The alkaline phosphatase human placental ALP processes BMS-751324 (10 μM; 0-60 min), whereas the chemical enzyme factory does not [1].

The drug BMS-751324 (1 mg/kg, 3 mg/kg; elbow; twice daily for one week) is used as a topological adjuvant for arthritis-related foot swelling. It is biotransformed in animals to produce BMS-582949 (suspension: 1 mg/kg-100 mg/kg, monkey: 10 or 30 mg/kg, 5 mL/kg methylcellulose suspension; and inhibits lipopolysaccharide-induced TNFα production [1]. Oral ; single dose) is administered to patients.

In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug 2 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug 1 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of 1 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, 2 demonstrated similar efficacy to 1. Most importantly, it was shown in clinical studies that prodrug 2 was indeed effective in addressing the pH-dependent absorption issue associated with 1.[2]

[1]. Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo [1, 2-f][1, 2, 4] triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases. Journal of Medicinal Chemistry, 2010, 53(18): 6629-6639.

[2]. Discovery of ((4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonyl)(propyl)carbamoyloxy)methyl-2-(4-(phosphonooxy)phenyl)acetate (BMS-751324), a Clinical Prodrug of p38α MAP Kinase Inhibitor. J Med Chem . 2015 Oct 8;58(19):7775-84.

This article describes the discovery and characterization of compound 7k (BMS-582949). 7k is a highly selective p38α MAP kinase inhibitor currently in a phase II clinical trial for the treatment of rheumatoid arthritis. The key to this discovery is the rational substitution of the N-methoxy group in the previously reported clinical candidate p38α inhibitor 1a with an N-cyclopropyl group. Unlike alkyl and other cycloalkyl groups, the sp2 hybridization of the cyclopropyl group can confer better hydrogen bonding properties to the directly substituted amide NH. Inhibitor 7k showed slightly lower p38α enzyme activity than 1a, but its pharmacokinetic properties were superior, thus showing higher efficacy in both acute mouse inflammation and pseudo-rat AA models. X-ray crystallography confirmed the binding mode of 7k to p38α [1]. The solubility of weakly basic compounds is affected by pH, and therefore their absorption is also affected by pH. In some cases, subtle changes in gastric pH can significantly modulate the plasma concentration of a drug and may result in drug exposure below therapeutic levels. Assessing the risks of pH-dependent absorption and potential drug interactions with pH adjusters is a crucial aspect of drug discovery and development. To assess the risk of reduced systemic drug exposure when used in combination with pH adjusters in clinical settings, pH effect studies are typically conducted, often in higher animals, primarily dogs. A major limitation of pH effect studies in higher animals lies in the resources and materials required to assess this risk. Consequently, these studies are largely limited to promising or mature lead compounds. In our current study, we qualitatively assessed the risks of pH-dependent absorption using in vitro water solubility assays, GastroPlus™ computer simulations, and an in vivo rat pH effect model. This paper evaluated the absorption of ketoconazole and atazanavir at different pH-dependent solubilities and predicted the varying degrees of influence of gastric pH on absorption based on in vitro, computer simulation, and in vivo experimental results. This prediction is consistent with findings from pH effect studies in higher species and humans. Subsequently, we extended this in vitro, computer simulation, and in vivo (IVISIV) correlation to assess pH absorption inhibition strategies. IVISIV predicts that the absorption of BMS-582949 is affected by pH, while its solubilizing prodrug BMS-751324 is expected to reduce this effect. Overall, this evaluation requires very little material, making this method more suitable for screening multiple compounds in lead compound optimization. https://pubmed.ncbi.nlm.nih.gov/25960252/

C32H35N6O10P

694.628268480301

694.215

C, 55.33; H, 5.08; N, 12.10; O, 23.03; P, 4.46

948842-66-8

44540113

Typically exists as solid at room temperature

1.5±0.1 g/cm3

1.676

1.22

4

13

15

49

1230

0

O=C(N(CCC)C(C1C(C)=C2N(N=CN=C2NC2C(C)=CC=C(C(NC3CC3)=O)C=2)C=1)=O)OCOC(CC1C=CC(OP(O)(O)=O)=CC=1)=O

XAYQDTPEOFCYIG-UHFFFAOYSA-N

InChI=1S/C32H35N6O10P/c1-4-13-37(32(42)47-18-46-27(39)14-21-6-11-24(12-7-21)48-49(43,44)45)31(41)25-16-38-28(20(25)3)29(33-17-34-38)36-26-15-22(8-5-19(26)2)30(40)35-23-9-10-23/h5-8,11-12,15-17,23H,4,9-10,13-14,18H2,1-3H3,(H,35,40)(H,33,34,36)(H2,43,44,45)

[[4-[5-(cyclopropylcarbamoyl)-2-methylanilino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carbonyl]-propylcarbamoyl]oxymethyl 2-(4-phosphonooxyphenyl)acetate

BMS-751324; 948842-66-8; 976Z3162LI; UNII-976Z3162LI; Benzeneacetic acid, 4-(phosphonooxy)-, 1-((((((4-((5-((cyclopropylamino)carbonyl)-2-methylphenyl)amino)-5-methylpyrrolo(2,1-f)(1,2,4)triazin-6-yl)carbonyl)propylamino)carbonyl)oxy)methyl) ester; (((4-((5-(cyclopropylcarbamoyl)-2-methylphenyl)amino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carbonyl)(propyl)carbamoyl)oxy)methyl 2-(4-(phosphonooxy)phenyl)acetate; [[4-[5-(cyclopropylcarbamoyl)-2-methylanilino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carbonyl]-propylcarbamoyl]oxymethyl 2-(4-phosphonooxyphenyl)acetate; [[4-[5-(cyclopropylcarbamoyl)-2-methylanilino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carbonyl]-propylcarbamoyl]oxymethyl 2-(4-phosphonooxyphenyl)acetate;BMS-751324 (BMS751324);Bms751324;

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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