| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
ACHN-975 targets LpxC (UDP-3-O-N-acetylglucosamine deacetylase), a key enzyme in the lipid A biosynthesis pathway of Gram-negative bacteria. Lipid A is the hydrophobic anchor of lipopolysaccharide (LPS), a critical component of the outer membrane of Gram-negative bacteria. By inhibiting LpxC, ACHN-975 disrupts LPS biosynthesis, compromising the integrity of the bacterial outer membrane and leading to bacterial cell death. The compound exhibits subnanomolar inhibitory activity against LpxC.
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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]. Targeting six strains of Pseudomonas aeruginosa, ACHN-975's minimum inhibitory concentrations (MIC) against 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. Zinc-dependent metalloamidase UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase is the bacterial enzyme known as LpxC [1].
ACHN-975 is a selective LpxC inhibitor with subnanomolar inhibitory activity. It effectively targets a broad spectrum of Gram-negative bacteria with low MIC values (≤1 µg/mL). The compound has an IC50 of 0.02 mM against Enterobacteriaceae. As a potent and selective LpxC inhibitor, ACHN-975 is a valuable tool for studying bacterial cell wall biosynthesis and for developing new antibiotics against multidrug-resistant Gram-negative pathogens. |
| ln Vivo |
Throughout the first four hours of therapy, bacterial titers steadily decreased in all dosage groups in response to ACHN-975 (ip; 5-30 mg/kg; single dose). 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].
ACHN-975 is effective against a broad spectrum of Gram-negative bacteria in vivo. Doses of 5-30 mg/kg have been evaluated in preclinical studies. However, detailed in vivo efficacy data including specific dosing regimens, infection models, and outcomes are limited in the publicly available literature. Further studies are needed to fully characterize its in vivo pharmacokinetics, efficacy, and safety profile. |
| Enzyme Assay |
In vitro enzyme inhibition assays using recombinant LpxC to determine IC50 values. The assay typically involves incubating LpxC with varying concentrations of ACHN-975 in the presence of the substrate (UDP-3-O-N-acetylglucosamine) and measuring the production of the deacetylated product using HPLC, mass spectrometry, or colorimetric methods. IC50 values are calculated from dose-response curves using non-linear regression analysis. Selectivity is assessed by testing ACHN-975 against a panel of related enzymes.
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| Cell Assay |
In vitro antibacterial susceptibility testing using broth microdilution or agar dilution methods to determine minimum inhibitory concentration (MIC) against a broad spectrum of Gram-negative bacterial strains (e.g., Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii). Bacterial cultures are grown to logarithmic phase, diluted to standard inoculum density, and incubated with serial dilutions of ACHN-975 at 37°C for 18-24 hours. MIC is determined as the lowest concentration inhibiting visible bacterial growth. Time-kill curve assays may be performed to assess bactericidal activity.
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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. ATCC 27853 strain. In vivo studies in animal models of Gram-negative bacterial infection (e.g., murine thigh infection model, sepsis model, or pneumonia model) to evaluate the efficacy of ACHN-975. ACHN-975 is administered via various routes (i.p., i.v., or s.c.) at doses ranging from 5-30 mg/kg. Bacterial burden in tissues (e.g., blood, spleen, lungs, or thighs) is measured by CFU counting. Survival rates are monitored. Pharmacokinetic parameters including bioavailability, half-life, protein binding, and tissue distribution are determined following administration. Toxicity studies are performed to assess safety. |
| 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. |
| Molecular Formula |
C20H23N3O4
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|---|---|
| Exact Mass |
369.168
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| CAS # |
1410809-36-7
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| Related CAS # |
ACHN-975 TFA;1410809-37-8
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| PubChem CID |
71466517
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
0.3
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
27
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| Complexity |
698
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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
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| InChi Key |
GOCUUDXEOKIQRU-IXDOHACOSA-N
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| InChi Code |
InChI=1S/C20H23N3O4/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/h7-10,15-17,24,27H,11-12,21H2,1-2H3,(H,22,25)(H,23,26)/t15-,16+,17-/m1/s1
|
| Chemical Name |
N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide
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| Synonyms |
ACHN 975 ACHN975 ACHN-975
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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.) |
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 |
| NCT01870245 | Terminated | Drug: ACHN-975 Drug: placebo |
Healthy Volunteer | Achaogen, Inc. | May 2013 | Phase 1 |
| NCT01597947 | Completed | Drug: ACHN-975 Drug: placebo |
Healthy Volunteer | Achaogen, Inc. | May 2012 | Phase 1 |
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