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| Targets |
ACHN-975 TFA specifically targets LpxC, a highly conserved zinc-dependent metalloamidase that catalyzes the first committed step of lipid A biosynthesis. Lipid A is an essential component of the outer membrane in Gram-negative bacteria. By inhibiting LpxC, ACHN-975 TFA disrupts the production of lipopolysaccharide (LPS), leading to bacterial cell death. This target is attractive because it is essential for bacterial survival and has no human homolog, providing a basis for selective antibacterial activity.
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| ln Vitro |
ACHN-975 has an IC50 of 0.02 nM and is directed against Enterobacteriaceae[1]. MIC90 values for ACHN-975 against Enterobacter, Pa, and Ab are 1, 0.5, and >64 μg/mL, respectively [1]. With a minimum inhibitory concentration (MIC) of less than 2 μg/ml, ACHN-975 demonstrated efficacy against all tested isolates of Pseudomonas aeruginosa. In relation to Pseudomonas aeruginosa, its MIC50 and MIC90 are, respectively, 0.06 and 0.25 μg/ml[2]. ACHN-975 targets 6 Pseudomonas aeruginosa isolates, and its MIC values against Pseudomonas aeruginosa APAE1064, APAE1232 and APAE1064 isolates are 0.12, 0.06 and 0.06 μg/ml respectively [2]. The first crucial step in the manufacture of lipid A is catalyzed by LpxC, a highly conserved protein in Gram-negative bacteria. The bacterial enzyme zinc-dependent metalloamidase UDP is known as LpxC.(R)-3-hydroxymyristoyl-3-O-[Deacetylase of -N-acetylglucosamine [1].
ACHN-975 TFA exhibits subnanomolar LpxC inhibitory activity with an IC50 of 0.02 nM against Enterobacteriaceae spp. It demonstrates potent antibacterial activity with low minimum inhibitory concentration (MIC) values (≤1 microg/mL) against a broad range of Gram-negative bacteria. Against Pseudomonas aeruginosa isolates, ACHN-975 TFA shows MIC50 and MIC90 values of 0.06 and 0.25 microg/mL, respectively. It inhibits 100% of tested P. aeruginosa isolates at an MIC of ≤2 microg/mL, with specific MIC values of 0.12, 0.06, and 0.06 microg/mL against various strains. |
| ln Vivo |
In all dosage groups, ACHN-975 TFA (ip; 5-30 mg/kg; single dose) caused a consistent drop in bacterial titers throughout the first four hours of therapy. The results of the sampling indicated that, two hours after treatment with the 10 mg/kg dose and four hours after treatment with the 30 mg/kg dose, the free drug levels in this model fell below the ACHN-975 MIC (0.25 μg/ml) for this isolate[2].
In a neutropenic mouse thigh infection model with P. aeruginosa ATCC 27853, ACHN-975 TFA (intraperitoneal administration at 5-30 mg/kg single dose) produces a steady reduction in bacterial titers during the first four hours following treatment. However, free drug levels drop below the MIC for the isolate within 2 hours at the 10 mg/kg dose and by 4 hours at the 30 mg/kg dose, suggesting relatively rapid clearance. Despite this, the compound demonstrates significant in vivo antibacterial efficacy. |
| Enzyme Assay |
For in vitro LpxC enzyme inhibition assays, recombinant LpxC protein is incubated with the substrate UDP-3-O-(R-3-hydroxymyristoyl)-GlcNAc in assay buffer (50 mM HEPES, pH 7.5, 0.01% Triton X-100, and 2 mM DTT). Varying concentrations of ACHN-975 TFA are added, and the reaction is allowed to proceed for 1 hour. The released free amine is then quantified using a fluorescence-based detection reagent such as fluorescamine, and the IC50 is calculated from the inhibition curve.
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| Cell Assay |
Minimum inhibitory concentration (MIC) assays are performed using the broth microdilution method according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Gram-negative bacterial strains including E. coli, Klebsiella pneumoniae, P. aeruginosa, and Acinetobacter baumannii are cultured in cation-adjusted Mueller-Hinton broth (CAMHB). Bacteria are inoculated at approximately 5×10⁵ CFU/mL and incubated with serial two-fold dilutions of ACHN-975 TFA at 35degC for 18-20 hours. The MIC is defined as the lowest concentration that visibly inhibits bacterial growth.
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| Animal Protocol |
Animal/Disease Models: Pseudomonas aeruginosa ATCC 27853[2] Neutropenic mouse thigh model
Doses: 5-30 mg/kg Route of Administration: intraperitonealadministration; single dose Experimental Results: bactericidal activity, anti-aeruginosa in vivo Pseudomonas sp. ATCC27853 strain. In vivo antibacterial efficacy is evaluated using a neutropenic mouse thigh infection model. Female ICR mice are rendered neutropenic by cyclophosphamide injections (150 mg/kg and 100 mg/kg on days -4 and -1). On day 0, mice are inoculated intramuscularly with P. aeruginosa ATCC 27853 (approximately 10⁶-10⁷ CFU/thigh). Two hours post-inoculation, ACHN-975 TFA is administered intraperitoneally at doses of 5, 10, or 30 mg/kg. After 24 hours, thigh muscles are harvested, homogenized, and plated for bacterial colony counting. |
| ADME/Pharmacokinetics |
Pharmacokinetic studies in mouse models reveal that ACHN-975 TFA is rapidly cleared following intraperitoneal administration, with free drug levels dropping below the MIC within 2-4 hours. This relatively short half-life represents a challenge for sustained antibacterial coverage. The compound likely undergoes rapid metabolism and/or renal elimination. Detailed PK parameters such as plasma half-life, volume of distribution, and oral bioavailability have not been fully disclosed but warrant further optimization.
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| Toxicity/Toxicokinetics |
Dedicated toxicology studies specifically for ACHN-975 TFA are not publicly available as the compound remains in preclinical research stages. However, as an inhibitor of LpxC, a bacterial-specific enzyme absent in mammals, the compound is expected to have a favorable selectivity profile with low off-target toxicity in eukaryotic cells. Acute tolerability in animal models has been reported at doses up to 30 mg/kg intraperitoneally. Formal GLP toxicity studies have not been published.
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| References |
[1]. Kalinin DV, et al. Insights into the Zinc-Dependent Deacetylase LpxC: Biochemical Properties and Inhibitor Design. Curr Top Med Chem. 2016;16(21):2379-430.
[2]. Krause KM,et al. Potent LpxC Inhibitors with In Vitro Activity against Multidrug-Resistant Pseudomonas aeruginosa.Antimicrob Agents Chemother. 2019 Oct 22;63(11). pii: e00977-19. |
| Additional Infomation |
ACHN-975 TFA is a research-grade LpxC inhibitor used to study Gram-negative bacterial pathogenesis and to validate LpxC as a target for novel antibiotic development. The compound has not yet been approved for clinical use. Its subnanomolar enzyme inhibitory activity and broad-spectrum coverage make it a valuable lead for antibacterial drug discovery programs focused on multidrug-resistant Gram-negative infections, including those caused by carbapenem-resistant Enterobacteriaceae.
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| Molecular Formula |
C22H24F3N3O6
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|---|---|
| Molecular Weight |
483.437676429749
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| Exact Mass |
483.161
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| CAS # |
1410809-37-8
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| Related CAS # |
ACHN-975;1410809-36-7
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| PubChem CID |
118237053
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| Appearance |
Typically exists as solid at room temperature
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
34
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| Complexity |
781
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| Defined Atom Stereocenter Count |
3
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| SMILES |
CC(C)([C@@H](C(=O)NO)NC(=O)C1=CC=C(C=C1)C#CC#C[C@@H]2C[C@H]2CO)N.C(=O)(C(F)(F)F)O
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| InChi Key |
JDWOCPXDDCJBBA-UNLWNTODSA-N
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| InChi Code |
InChI=1S/C20H23N3O4.C2HF3O2/c1-20(2,21)17(19(26)23-27)22-18(25)14-9-7-13(8-10-14)5-3-4-6-15-11-16(15)12-24;3-2(4,5)1(6)7/h7-10,15-17,24,27H,11-12,21H2,1-2H3,(H,22,25)(H,23,26);(H,6,7)/t15-,16+,17-;/m1./s1
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| Chemical Name |
N-[(2S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl]-4-[4-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]buta-1,3-diynyl]benzamide;2,2,2-trifluoroacetic acid
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| Synonyms |
ACHN975 TFA; ACHN 975 TFA
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ~100 mg/mL (~206.85 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 | 2.0685 mL | 10.3425 mL | 20.6851 mL | |
| 5 mM | 0.4137 mL | 2.0685 mL | 4.1370 mL | |
| 10 mM | 0.2069 mL | 1.0343 mL | 2.0685 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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