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.

Physicochemical Properties

Molecular Formula	C18H21N5O3
Molecular Weight	355.391043424606
Exact Mass	355.164
Elemental Analysis	C, 60.83; H, 5.96; N, 19.71; O, 13.51
CAS #	1494675-86-3
Related CAS #	1494675-86-3
PubChem CID	72792692
Appearance	Solid powder
Density	1.3±0.1 g/cm3
Boiling Point	691.6±55.0 °C at 760 mmHg
Flash Point	372.1±31.5 °C
Vapour Pressure	0.0±2.3 mmHg at 25°C
Index of Refraction	1.650
LogP	1.37
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	6
Heavy Atom Count	26
Complexity	480
Defined Atom Stereocenter Count	0
SMILES	O=C(C1=CN(CC2=NC=NC(OC)=C2C)C3=CC(C)=CN=C31)NCCO
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
Synonyms	AZ7371;TBA7371;AZ-7371;TBA 7371;AZ 7371; TBA-7371
HS Tariff Code	2934.99.03.00
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

Targets	DprE1
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.
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.
Animal Protocol	Rodent model of tuberculosis; Oral
References	[1]. J Med Chem.2014 Jul 10;57(13):5728-37 [2]. Antimicrob Agents Chemother.2014 Sep;58(9):5325-31. [3]. Chem Cent J. 2018 Jun 23;12(1):72.
Additional Infomation	TBA-7371 is under investigation in clinical trial NCT04176250 (Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis).

Solubility Data

Solubility (In Vitro)

DMSO: ~25 mg/mL (~70.35 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	2.8138 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.