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Purity: ≥98%
DprE1-IN-1 (AZ-7371;TBA-7371), a1,4-azaindole analog, is a potent andnoncovalentinhibitor of decaprenylphosphoryl-β-d-ribose-2'-epimerase (DprE1) with a potential to become a drug candidate for treatment of tuberculosis. It inhibits DprE1 with ic50 of 10 nM; it also inhibits PDE6 with IC50 of 6 uM. Itdemonstrats efficacy in a rodent model of tuberculosis, making it promising for further development. DprE1-IN-1 hasexcellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-β-d-ribose-2'-epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. In summary,DprE1-IN-1is a promising candidate for the development of a novel anti-TB drug.
| Targets |
DprE1
DprE1-IN-1 (AZ7371; TBA7371) targets decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) of Mycobacterium tuberculosis, acting via noncovalent inhibition[1] DprE1-IN-1 (AZ7371; TBA7371) is a 1,4-azaindole derivative targeting Mycobacterium tuberculosis DprE1 [2] DprE1-IN-1 (AZ7371; TBA7371) is classified as a 1,4-azaindole-based inhibitor of DprE1[3] |
|---|---|
| ln Vitro |
DprE1-IN-1, a1,4-azaindole analog, is a potent inhibitor of decaprenylphosphoryl-β-d-ribose-2-epimerase (DprE1) with ic50 of 10 nM; it also inhibits PDE6 with IC50 of 6 uM. Itdemonstrats efficacy in a rodent model of tuberculosis, making it promising for further development. DprE1-IN-1 hasexcellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-β-d-ribose-2-epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. In summary,DprE1-IN-1is a promising candidate for the development of a novel anti-TB drug.Kinase Assay:DprE1-IN-1, a1,4-azaindole analog, is a potent inhibitor of decaprenylphosphoryl-β-d-ribose-2-epimerase (DprE1) with ic50 of 10 nM; it also inhibits PDE6 with IC50 of 6 uM.
1. DprE1-IN-1 (AZ7371; TBA7371) belongs to the 1,4-azaindole series with potent in vitro antimycobacterial activity via noncovalent inhibition of M. tuberculosis DprE1; the series was optimized to reduce phosphodiesterase 6 (PDE6) off-target activity while maintaining anti-M. tuberculosis potency [1] 2. Compound 2 (a lead compound of the 1,4-azaindole series including DprE1-IN-1 (AZ7371; TBA7371)) exhibited potent in vitro cellular activity against M. tuberculosis; it showed no antagonistic activity with other anti-TB drugs (e.g., PA824, TMC207) and displayed synergy with PA824 and TMC207 in vitro (fractional MICs and F_A/F_B values were measured, with <200 CFU/ml recovered for PA824 combination) [2] 3. DprE1-IN-1 (AZ7371; TBA7371) is a noncovalent DprE1 inhibitor; DprE1 catalyzes the FAD-dependent epimerization reaction in arabinose biosynthesis (a key component of the mycobacterial cell wall), and inhibition of DprE1 blocks mycobacterial cell wall synthesis [3] |
| ln Vivo |
DprE1-IN-1 demonstrats efficacy in a rodent model of tuberculosis, making it promising for further development.The pharmacokinetic profile of DprE1-IN-1 as a representative of the series in mice, rats, and dogs was determined after i.v. and oral dosing. DprE1-IN-1 shows oral bioavailabilities of 86% and 100% in rats and dogs, respectively. The oral exposures of DprE1-IN-1, assessed in infected animals, shows AUCs ranging from 166 to 240 μM · h, and free plasma concentrations were maintained above the MIC for 10 to 24 h.
1. The 1,4-azaindole series (including DprE1-IN-1 (AZ7371; TBA7371)) showed excellent in vivo antimycobacterial potency before optimization, but high mouse metabolic turnover limited its advancement; optimized 1,4-azaindole compounds demonstrated efficacy in a rat chronic TB infection model [1] 2. Compound 2 (a lead compound of the 1,4-azaindole series including DprE1-IN-1 (AZ7371; TBA7371)) exhibited efficacy in BALB/c mouse and Wistar rat chronic TB infection models: - In BALB/c mice with chronic TB infection, oral administration of compound 2 at 300 mg/kg (6 days/week for 4 weeks) resulted in a statistically significant net log₁₀ CFU/lung reduction (P < 0.05) compared to vehicle-treated controls (early control: 6.0 ± 0.08 log₁₀ CFU/lung; late control: 6.24 ± 0.12 log₁₀ CFU/lung); combination with TMC207 translated in vitro synergy to in vivo efficacy, while combination with PA824 also showed efficacy [2] - In Wistar rats with chronic TB infection, oral administration of compound 2 (6 days/week for 4 weeks) resulted in a statistically significant net log₁₀ CFU reduction/left lobe of the lung (P < 0.05) compared to vehicle-treated controls (early control: 6.02 ± 0.11 log₁₀ CFU/lung; late control: 6.41 ± 0.20 log₁₀ CFU/lung) [2] |
| Animal Protocol |
Rodent model of tuberculosis; Oral
1. Rat chronic TB infection model: Optimized 1,4-azaindole compounds (including DprE1-IN-1 (AZ7371; TBA7371)) were administered to rats (route/frequency/dosage not detailed) to evaluate in vivo antimycobacterial efficacy [1] 2. BALB/c mouse chronic TB infection model: Compound 2 (a lead 1,4-azaindole including DprE1-IN-1 (AZ7371; TBA7371)) was administered orally at 30, 100, and 300 mg/kg (6 days/week for 4 weeks); lung bacterial counts (log₁₀ CFU/lung) were measured to assess efficacy, and time-concentration profiles of the compound (alone and in combination with PA824/TMC207) were determined [2] 3. Wistar rat chronic TB infection model: Compounds 1 and 2 (1,4-azaindole series including DprE1-IN-1 (AZ7371; TBA7371)) were administered orally at 100 mg/kg (6 days/week for 4 weeks); bacterial counts in the left lobe of the lung (log₁₀ CFU) were quantified, and time-concentration profiles of the compounds were measured [2] |
| ADME/Pharmacokinetics |
1. The initial 1,4-azaindole series compounds (including DprE1-IN-1 (AZ7371; TBA7371)) had high metabolic turnover in mice; lead compound optimization improved metabolic stability and yielded compounds with good pharmacokinetic characteristics [1]
2. Compound 2 (a lead compound 1,4-azaindole, including DprE1-IN-1 (AZ7371; TBA7371)) has drug-like pharmacokinetic characteristics; its time-concentration curves were determined in mice with chronic Mycobacterium tuberculosis infection (oral doses of 30/100/300 mg/kg and 100 mg/kg, respectively) and rats (oral dose of 100 mg/kg); the human clearance of compound 2 was predicted to be low, and the predicted human dose was ≤1 g/day [2] |
| Toxicity/Toxicokinetics |
1. The initial 1,4-azaindole series of compounds (including DprE1-IN-1 (AZ7371; TBA7371)) exhibit PDE6 off-target activity [1]
2. Compound 2 (a lead 1,4-azaindole compound, including DprE1-IN-1 (AZ7371; TBA7371)) has extremely low in vitro safety risk; however, no data on LD50, hepatotoxicity, nephrotoxicity, drug interactions, or plasma protein binding were provided [2] |
| References | |
| Additional Infomation |
TBA-7371 is being studied in the clinical trial NCT04176250 (early bactericidal activity of TBA-7371 in pulmonary tuberculosis).
1. DprE1-IN-1 (AZ7371; TBA7371) is a 1,4-azaindole derivative and a non-covalent inhibitor of Mycobacterium tuberculosis DprE1; the lead compound optimization solved the problems of metabolic instability and PDE6 off-target activity, making this series of compounds suitable for in vivo combination therapy and safety studies[1] 2. Compound 2 (including DprE1-IN-1 (AZ7371; TBA7371) and other 1,4-azaindole lead compounds) is a promising clinical candidate drug for tuberculosis treatment, with strong cellular activity, drug-like properties and efficacy in chronic tuberculosis infection models; it shows synergistic effects with PA824/TMC207 and no antagonistic effects with other anti-tuberculosis drugs[2] 3. DprE1 is a key target for the development of anti-tuberculosis drugs (in 2009) Discovered in 1990), it participates in the biosynthesis of arabinose (which is crucial for the formation of mycobacterial cell walls); DprE1-IN-1 (AZ7371; TBA7371) is a non-covalent DprE1 inhibitor based on 1,4-azaindole, but the clinical progress of DprE1 inhibitors faces challenges (currently, no DprE1 inhibitor has completed phase II clinical trials) [3] |
| Molecular Formula |
C18H21N5O3
|
|---|---|
| Molecular Weight |
355.391043424606
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| Exact Mass |
355.164
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| Elemental Analysis |
C, 60.83; H, 5.96; N, 19.71; O, 13.51
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| CAS # |
1494675-86-3
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| Related CAS # |
1494675-86-3
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| PubChem CID |
72792692
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| Appearance |
Solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
691.6±55.0 °C at 760 mmHg
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| Flash Point |
372.1±31.5 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.650
|
| LogP |
1.37
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
26
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| Complexity |
480
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1=CN(CC2=NC=NC(OC)=C2C)C3=CC(C)=CN=C31)NCCO
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| InChi Key |
VDRYGTNDKXIPSK-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C18H21N5O3/c1-11-6-15-16(20-7-11)13(17(25)19-4-5-24)8-23(15)9-14-12(2)18(26-3)22-10-21-14/h6-8,10,24H,4-5,9H2,1-3H3,(H,19,25)
|
| Chemical Name |
N-(2-hydroxyethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
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| Synonyms |
AZ7371;TBA7371;AZ-7371;TBA 7371;AZ 7371; TBA-7371
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| HS Tariff Code |
2934.99.03.00
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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: ~25 mg/mL (~70.35 mM)
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|---|---|
| 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
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] 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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8138 mL | 14.0691 mL | 28.1381 mL | |
| 5 mM | 0.5628 mL | 2.8138 mL | 5.6276 mL | |
| 10 mM | 0.2814 mL | 1.4069 mL | 2.8138 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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