LT052 (LT-052) is a novel and potent BET BD1 inhibitor with anti-inflammatory activity. It mediates BRD4/NF-B/NLRP3 signaling pathways with comparable protein expression. It significantly relieves gout arthritis symptoms in a rat model.
Physicochemical Properties
| Molecular Formula | C22H19N5O4S |
| Molecular Weight | 449.4824 |
| Exact Mass | 449.115 |
| CAS # | 2543545-44-2 |
| Related CAS # | LT052 HCl;2543545-44-2; |
| PubChem CID | 145925666 |
| Appearance | Yellow to orange solid powder |
| LogP | 2.3 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 32 |
| Complexity | 820 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | S(C1=C([H])C([H])=C([H])C([H])=C1OC([H])([H])[H])(N([H])C1C([H])=C([H])C2=C3C=1N=C(C([H])=C3C(N2C([H])([H])[H])=O)N1C([H])=NC(C([H])([H])[H])=C1[H])(=O)=O |
| InChi Key | FSMTUHGXWGJNKK-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C22H19N5O4S/c1-13-11-27(12-23-13)19-10-14-20-16(26(2)22(14)28)9-8-15(21(20)24-19)25-32(29,30)18-7-5-4-6-17(18)31-3/h4-12,25H,1-3H3 |
| Chemical Name | 2-methoxy-N-[2-methyl-6-(4-methylimidazol-1-yl)-3-oxo-2,7-diazatricyclo[6.3.1.04,12]dodeca-1(12),4,6,8,10-pentaen-9-yl]benzenesulfonamide |
| Synonyms | LT052 LT-052 |
| 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) |
Biological Activity
| ln Vitro | Nitric oxide (NO) production in RAW264.7 cells and NF-κB transcriptional activity in HUVEC cells are both inhibited by LT052 (1 μM) (inhibition rate: 101.89%). When LT052's anti-inflammatory activity was evaluated in vitro against the protein's poor activity, it exhibited anti-inflammatory activity that was on par with or superior to that of the pan-BET inhibitor (JQ1) [1]. With respect to BRD4(1) (IC50: 87.7±4.9 nM), BRD3(1) (IC50: 246.3±20.2 nM), and BRDT(1) (IC50: 357.1±8.3 nM), LT052 exhibits strong inhibitory activity. Additionally, LT052 inhibits BRPF1b (IC50: 567.5±16.9 nM). Furthermore, LT052 has a Kd of >25 μM for BD2 and 105 nM for BD1, making it 238 times more selective for BD1 than BD2 [1]. LT052 (1 μM; 1 h) blocks the BRD4/NF-κB/NLRP3 signaling pathway to prevent MSU-induced pyroptosis in THP-1 cells [1]. |
| ln Vivo | In MSU-induced acute gouty arthritis, LT052 (1 mg/kg; intra-articular injection) has a good therapeutic effect by inhibiting severe neutrophil infiltration and synovial hyperplasia [1]. In rat synovial tissue, LT052 prevents macrophage pyroptosis via controlling the BRD4/NF-κB/NLRP3 signaling pathway [1]. In liver microsomes from several species (human, monkey, dog, and rat), LT052 exhibits high clearance; the range of clearance is 93.517 µL/min/mg protein to 146.685 µL/min/mg protein. Hepatic microsomal metabolism in vitro is generally reasonably stable in LT052 [1]. |
| Animal Protocol |
Animal/Disease Models: Male adult SD (SD (Sprague-Dawley)) rat (250-280 g) (animal model of acute gouty arthritis) [1] Doses: 1 mg/kg Route of Administration: Intra-articular injection Experimental Results:Restore joint circumference to normal level. |
| References |
[1]. Discovery of Benzo[cd]indol-2(1H)-ones and Pyrrolo[4,3,2-de]quinolin-2(1H)-ones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain with Potential High Efficiency against Acute Gouty Arthritis. J Med Chem. 2019 Dec 26;62(24):11080-11107. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~10.42 mg/mL (~23.18 mM) |
| Solubility (In Vivo) |
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. Injection Formulations (e.g. IP/IV/IM/SC) 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). 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) Oral Formulations 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). 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 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2248 mL | 11.1240 mL | 22.2479 mL | |
| 5 mM | 0.4450 mL | 2.2248 mL | 4.4496 mL | |
| 10 mM | 0.2225 mL | 1.1124 mL | 2.2248 mL |