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Physicochemical Properties
| Molecular Formula | C11H14N4O5S |
| Molecular Weight | 314.317660808563 |
| Exact Mass | 314.07 |
| Elemental Analysis | C, 42.03; H, 4.49; N, 17.83; O, 25.45; S, 10.20 |
| CAS # | 1001404-83-6 |
| PubChem CID | 23653540 |
| Appearance | White to off-white solid powder |
| LogP | -0.6 |
| Hydrogen Bond Donor Count | 0 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 2 |
| Heavy Atom Count | 21 |
| Complexity | 597 |
| Defined Atom Stereocenter Count | 3 |
| SMILES | S1([C@@H]2CC(N2[C@@H](C(=O)[O-])[C@]1(C)CN1C=C[N+](C)=N1)=O)(=O)=O |
| InChi Key | HFZITXBUTWITPT-YWVKMMECSA-N |
| InChi Code | InChI=1S/C11H14N4O5S/c1-11(6-14-4-3-13(2)12-14)9(10(17)18)15-7(16)5-8(15)21(11,19)20/h3-4,8-9H,5-6H2,1-2H3/t8-,9+,11+/m1/s1 |
| Chemical Name | (2S,3S,5R)-3-methyl-3-((3-methyl-1H-1,2,3-triazol-3-ium-1-yl)methyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide |
| Synonyms | AAI-101, Enmetazobactam;AAI-101; AAI-101; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.(2). Please store this product in a sealed and protected environment (e.g. under nitrogen), 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) |
Biological Activity
| ln Vitro | Enmetazobactam has a MIC50 of 0.125 mg/L and a MIC90 of 64 mg/L, which indicates its strong activity against particular resistance phenotypes. For the majority of strains, cefepime-Enmetazobactam MICs decrease as Enmetazobactam concentrations rise (from 1 to 16 mg/L), indicating that Enmetazobactam's concentration affects the cephalosporin's ability to fight bacteria[1]. |
| ln Vivo | Bacterial density reductions of ≥0.5 log10 CFU and ≥1 log10 CFU are observed in neutropenic animals after treatment with cefepime-Enmetazobactam for 12 out of the 20 tested strains. Only four strains exhibit increases in bacterial density, and regardless of the concentration of Enmetazobactam, three of these strains have cefepime-Enmetazobactam MICs of ≥64 mg/L[2]. |
| Animal Protocol | Each of the 20 Enterobacteriaceae strains is used to infect three mouse groups. Mice are given humanized cefepime or cefepime-AAI101 treatment regimens two hours after being injected. Subcutaneous injections of 0.2 mL are used to administer each dose. Another set of mice receives normal saline through the same route, at the same volume, and on the same frequency to act as control animals. All animals have their thighs taken 24 hours after treatment starts. All study mice were harvested by first being put to sleep with CO2 exposure and then having their cervical dislocations. Thighs are removed from the sacrifice and homogenized one at a time in regular saline. Using a spiral plater, serial dilutions of thigh homogenates are spread onto Trypticase soy agar containing 5% sheep blood in order to calculate the number of CFU. A third group of three infected but untreated mice is harvested at the start of dosing and used as a 0-hour control, in addition to the previously mentioned treatment and control groups. The measurement of the change in the log10 number of CFU obtained in mice after 24 hours of treatment from the densities observed in the 0-hour control animals determines the efficacy, which is expressed as the change in bacterial density. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion The mean (SD) Cmax is 19.8 (6.3) µg/mL in patients with cUTI and eGFR greater than or equal to 60 mL/min. The mean AUC0-last is 75.3 (30.8) μgxh/mL. About 90% of enmetazobactam is excreted unchanged in urine. Mean (SD) steady state volume of distribution (Vss) is 25.26 (9.97) L in patients with cUTI and eGFR greater than or equal to 60 mL/min.. The mean (SD) clearance is 7.6 (2.9) L/h in patients with cUTI and eGFR greater than or equal to 60 mL/min. Metabolism / Metabolites Enmetazobactam is minimally metabolized. Biological Half-Life The mean (SD) half-life is 2.6 (1.1) hours in patients with cUTI and eGFR greater than or equal to 60 mL/min. |
| Toxicity/Toxicokinetics |
Protein Binding The percent protein binding of enmetazobactam is negligible. |
| References |
[1]. In Vitro Activity of Cefepime/AAI101 and Comparators against Cefepime Non-susceptible Enterobacteriaceae. Pathogens. 2015 Aug 18;4(3):620-5. [2]. In vivo activities of simulated human doses of cefepime and cefepime-AAI101 against multidrug-resistant Gram-negative Enterobacteriaceae. Antimicrob Agents Chemother. 2015 May;59(5):2688-94. |
| Additional Infomation |
Enmetazobactam is a penicillanic acid sulfone extended-spectrum beta (β)-lactamase (ESBL) inhibitor. Because ESBL enzymes can hydrolyze important antibiotics such as penicillins, broad-spectrum cephalosporins and monobactams, ESBL-producing bacteria poses challenges in the treatment of serious infections. The combination product of enmetazobactam and [cefepime] was first approved by the FDA on February 23, 2024, for the treatment of complicated urinary tract infections. Enmetazobactam is used as cefepime-sparing therapy by preventing its breakdown by ESBL. Drug Indication In combination with [cefepime], enmetazobactam is indicated for the treatment of adults with complicated urinary tract infections (cUTI) including pyelonephritis caused by designated susceptible microorganisms. Mechanism of Action Extended-spectrum beta-lactamases (ESBLs) are a group of bacterial serine beta-lactamases that hydrolyze third-generation cephalosporins (3GC), leading to the development of 3GC-resistant bacteria. When used in combination with cefepime, enmetazobactam protects cefepime from degradation by ESBLs and prevents antibiotic resistance. Pharmacodynamics Enmetazobactam is an antibacterial agent that is active against most gram-positive and gram-negative bacteria. |
Solubility Data
| Solubility (In Vitro) | DMSO : ≥ 113.3 mg/mL (~360.46 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.62 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (6.62 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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. Solubility in Formulation 3: ≥ 2.08 mg/mL (6.62 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 10% DMSO+90% (20% SBE-β-CD in Saline): ≥ 2.08 mg/mL (6.62 mM) (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1815 mL | 15.9074 mL | 31.8147 mL | |
| 5 mM | 0.6363 mL | 3.1815 mL | 6.3629 mL | |
| 10 mM | 0.3181 mL | 1.5907 mL | 3.1815 mL |