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Purity: ≥98%
Telacebec (Q203; IAP6) is an imidazopyridine amide (IAP) compound that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. It has the potential for the treatment of tuberculosis. Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of Q203. Q203 is active against the reference strain Mycobacterium tuberculosis H37Rv with MIC50s of 2.7 nM in culture broth medium and 0.28 nM inside macrophages. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, these data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.
| Targets |
Mycobacterium tuberculosis H37Rv( MIC50=2.7 nM )
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| ln Vitro |
Telacebec (Q203; IAP6) is an imidazopyridine amide (IAP) compound that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. It has the potential for the treatment of tuberculosis. Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of Q203. Q203 is active against the reference strain Mycobacterium tuberculosis H37Rv with MIC50s of 2.7 nM in culture broth medium and 0.28 nM inside macrophages. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, these data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.
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| ln Vivo |
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| Enzyme Assay |
Q203 is active against the reference strain Mycobacterium tuberculosis H37Rv with MIC50s of 2.7 nM in culture broth medium and 0.28 nM inside macrophages.
Microsomal stability assay. [1] Compounds (2 μM final in 0.2% DMSO) were incubated with 0.5 mg mL−1 human (pool of 200, mixed gender), male dog, male rat or male mouse liver microsomes in potassium phosphate buffer. The reaction was initiated by the addition of NADPH and stopped either immediately or at 10, 20, 30 or 60 min for a precise estimate of clearance. A triple quadrupole Quattro Premier mass spectrometer with electrospray ionization (ESI) was employed for sample analysis. Samples were passed through trapping cartridges (Acquity BEH RP18 50 mm × 2.1 mm, 1.7 μm, Waters, Milford, MA) followed by an analytical column. The percentage of remaining compound was calculated by comparing with the initial quantity at 0 min. Half-life was then calculated using first-order reaction kinetics. CYP450 inhibition assays. [1] The assay used individual fluorescent probe substrates with individual recombinant human cytochrome P450 (rhCYP) isozymes and a fluorescent detection according to previously published methods36. The probe substrates (in 0.5% DMSO) used for each isozyme were as follows: 7-benzyloxy-4-(trifluoromethyl)-coumarin for CYP3A4, 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4-methylcoumarin (AMMC) for CYP2D6, 3-cyano-7-ethoxycoum (CEC) for 1A2 and 2C19 and 7-methoxy-4-(trifluoromethyl)-coumarin (MFC) for 2C9. Fluorescence was measured using Victor3 V multilabel plate reader. The IC50 was determined using an eight-point concentration curve with threefold serial dilution. |
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| Cell Assay |
High-content screening assay in infected macrophages.[1]
The assay was performed as previously described9,30. Briefly, Raw 264.7 cells were infected with M. tuberculosis H37Rv-GFP at a multiplicity of infection of 2:1 and dispensed into 384-well plates. After 5 d of infection, macrophages were stained with Syto 60. Image acquisition was performed on an EVOscreen Mark III platform integrated with Opera. Bacterial load and macrophage number were quantified using proprietary image analysis software. Minimum inhibitory concentration determination.[1] H37Rv-GFP was dispensed into 384-well plates in 7H9 medium without glycerol. Mycobacterial growth was determined by measuring fluorescence intensity at 488 nm after 5 d of incubation. Alternatively, the MICs were determined using the resazurin susceptibility assay or a turbidity-based assay in 384-well plates. The MIC50 were determined using an eight- or ten-point concentration curve with threefold serial dilution. Cytotoxicity.[1] Cytotoxicity was tested against the human cell lines SH-SY5Y (brain), HEK293 (kidney) and HepG2 (liver) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) viability assay as previously described. ATP depletion assay on M. tuberculosis H37Rv.[1] M. tuberculosis H37Rv was exposed to the test compounds for 24 h (aerobiosis) or 5 d (anaerobiosis), mixed with an equal volume of BacTiter-Glo reagent and incubated in the dark for 10 min. Luminescence was recorded on a Victor3 V multilabel plate reader. |
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| Additional Infomation |
New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis, several of which are currently in clinical trials. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.[1]
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| Molecular Formula |
C29H28CLF3N4O2
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|---|---|
| Molecular Weight |
557.01
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| Exact Mass |
556.19
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| Elemental Analysis |
C, 62.53; H, 5.07; Cl, 6.36; F, 10.23; N, 10.06; O, 5.74
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| CAS # |
1334719-95-7
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| Related CAS # |
1334719-95-7;1566517-83-6 (Ditosylate);
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| PubChem CID |
68234908
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.615
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| LogP |
7.32
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| SMILES |
CCC1=C(N2C=C(C=CC2=N1)Cl)C(=O)NCC3=CC=C(C=C3)N4CCC(CC4)C5=CC=C(C=C5)OC(F)(F)F
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| InChi Key |
OJICYBSWSZGRFB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C29H28ClF3N4O2/c1-2-25-27(37-18-22(30)7-12-26(37)35-25)28(38)34-17-19-3-8-23(9-4-19)36-15-13-21(14-16-36)20-5-10-24(11-6-20)39-29(31,32)33/h3-12,18,21H,2,13-17H2,1H3,(H,34,38)
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| Chemical Name |
6-chloro-2-ethyl-N-[[4-[4-[4-(trifluoromethoxy)phenyl]piperidin-1-yl]phenyl]methyl]imidazo[1,2-a]pyridine-3-carboxamide
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| Synonyms |
Q-203 free base; Q 203; Telacebec; 1334719-95-7; Q203; Q-203; 6-chloro-2-ethyl-n-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide; MMV687696; 55G92WGH3X; CHEMBL3298910;
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| HS Tariff Code |
2934.99.9001
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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: ~20 mg/mL ( 35.9 mM)
Water: ~20 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2 mg/mL (3.59 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 sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7953 mL | 8.9765 mL | 17.9530 mL | |
| 5 mM | 0.3591 mL | 1.7953 mL | 3.5906 mL | |
| 10 mM | 0.1795 mL | 0.8977 mL | 1.7953 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04847583 | Terminated | Drug: Q203 | COVID-19 Virus Infection | Qurient Co., Ltd. | July 29, 2021 | Phase 2 |
| NCT03563599 | Completed | Drug: Telacebec (Q203) | Treatment-naïve, Sputum Smear-positive Patients With Drug-sensitive Pulmonary TB | Qurient Co., Ltd. | July 23, 2018 | Phase 2 |
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