Avibactam tomilopil (ARX-1796, AV-006) is an Avibactam precursor and an orally bioavailable β-lactamase inhibitor. Avibactam has an inhibitory profile against class A and class C beta-lactamases such as ESBLs, AmpC, and Klebsiella pneumoniae carbapenemase (KPC) enzymes. AVIBACTAM TOMILOPIL is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.

Physicochemical Properties

Molecular Formula	C14H23N3O8S
Molecular Weight	393.41
Exact Mass	393.12
Elemental Analysis	C, 42.74; H, 5.89; N, 10.68; O, 32.53; S, 8.15
CAS #	2245880-46-8
PubChem CID	135339165
Appearance	White to off-white solid powder
LogP	-0.2
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	9
Heavy Atom Count	26
Complexity	687
Defined Atom Stereocenter Count	2
SMILES	C(OCC)(=O)C(C)(C)COS(ON1C(=O)[N@@]2C[C@@]1([H])CC[C@H]2C(N)=O)(=O)=O
InChi Key	JHSLCXRZVJOZQZ-ZJUUUORDSA-N
InChi Code	InChI=1S/C14H23N3O8S/c1-4-23-12(19)14(2,3)8-24-26(21,22)25-17-9-5-6-10(11(15)18)16(7-9)13(17)20/h9-10H,4-8H2,1-3H3,(H2,15,18)/t9-,10+/m1/s1
Chemical Name	ethyl 3-[[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]oxysulfonyloxy]-2,2-dimethylpropanoate
Synonyms	Avibactam tomilopil; ARX-1796; 2245880-46-8; AV-006; PF-07338233; ethyl 3-[[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]oxysulfonyloxy]-2,2-dimethylpropanoate; avibactam tomilopil [INN]; Avibactam tomilopil [WHO-DD];
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
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	TEM-1; CTX-M-15
ln Vivo	The treatment of urinary tract infections (UTIs) has been complicated by the emergence of multidrug-resistant, β-lactamase-expressing pathogens. As a result of the limited treatment options, patients often require hospitalization and intravenous therapy. In essence, a strong unmet need for oral antibiotics, active against extended-spectrum β-lactamase (ESBL) uropathogens has emerged. Oral carbapenems (tebipenem and sulopenem) and oral cephalosporin/β-lactamase inhibitor combinations are in various stages of clinical development for the treatment of uncomplicated and complicated UTI. Tebipenem, if approved, will be the first oral treatment for complicated UTI while sulopenem will be for uncomplicated UTI. The β-lactamase inhibitors ETX0282, VNRX7145, Avibactam tomilopil (ARX-1796; AV-006), and QPX7728 are combined with cefpodoxime proxetil or ceftibuten that achieve favorable exposures in urine compared to other uropathogen-active oral cephalosporins. The combination ceftibuten-QPX7728 has potential broad-spectrum coverage against carbapenemase producers including metallo β-lactamase producers. Other novel combinations, namely cefpodoxime/ETX0282, ceftibuten/VNRX-7145, and ceftibuten/Avibactam tomilopil (ARX-1796; AV-006), have also demonstrated excellent activity against Klebsiella pneumoniae carbapanemase (KPC) and OXA-48-like producers. All these agents, upon their arrival for commercial use, would strengthen the outpatient therapy [1].
ADME/Pharmacokinetics	Avibactam is a potent DBO inhibitor of class A, C, and some D β-lactamases approved for IV dosing in combination with ceftazidime by the FDA in 2015, but the oral bioavailability of avibactam is negligible (ca. 7%). To expand the clinical utility of avibactam, Arixa Pharmaceuticals has discovered a novel orally administered avibactam prodrug (ARX-1796/AV-006). The prodrug ARX-1796 has been shown to have an oral bioavailability of 60–80% in phase 1 studies. The oral β-lactams ceftibuten, cefixime, amoxicillin, cefpodoxime, sulopenem, and tebipenem were evaluated in combination with ARX-1796 against Enterobacterales expressing ESBL, ampC, KPC, and OXA-48-like. Ceftibuten with ARX-1796 showed lower MICs compared to other combinations. Addition of ARX-1796 to ceftibuten retained its potent activity against KPC and OXA-48-like producers with the low MIC50/90 of 0.06/0.5 mg/L and 0.06/0.25 mg/L, respectively. Interestingly, pharma giant Pfizer took over Arixa Pharmaceuticals recently.[1]
References	[1]. Oral Antibiotics in Clinical Development for Community-Acquired Urinary Tract Infections. Infect Dis Ther. 2021;10(4):1815-1835. [2]. Spotlight on ceftazidime/avibactam: a new option for MDR Gram-negative infections. J Antimicrob Chemother. 2016;71(10):2713-2722.
Additional Infomation	During the last decade infections caused by MDR Gram-negative bacteria (GNB) have become increasingly prevalent. Because of their high morbidity and mortality rates, these infections constitute a serious threat to public health worldwide. Ceftazidime/avibactam is a new approved agent combining ceftazidime and a novel β-lactamase inhibitor with activity against various β-lactamases produced by MDR GNB. Avibactam has a spectrum of inhibition of class A and C β-lactamases, including ESBLs, AmpC and Klebsiella pneumoniae carbapenemase (KPC) enzymes. Thus, combination with this inhibitor expands ceftazidime's spectrum of activity to MDR Enterobacteriaceae and Pseudomonas aeruginosa strains. In Phase II clinical trials of patients with complicated intra-abdominal infections and complicated urinary tract infections ceftazidime/avibactam exhibited clinical efficacy comparable to those of meropenem and imipenem/cilastatin, respectively. A Phase III clinical trial confirmed the efficacy of ceftazidime/avibactam in patients with MDR Enterobacteriaceae and P. aeruginosa infections. Microbiological surveillance studies, in vivo animal models of infection and pharmacokinetic/pharmacodynamic target attainment analyses are also discussed, to assess the potential role of this new drug in the treatment of infections caused by MDR GNB.[2]

Solubility Data

Solubility (In Vitro)

DMSO : 100 mg/mL (254.19 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.35 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 25.0 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: ≥ 2.5 mg/mL (6.35 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 25.0 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (6.35 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.5419 mL	12.7094 mL	25.4188 mL
	5 mM	0.5084 mL	2.5419 mL	5.0838 mL
	10 mM	0.2542 mL	1.2709 mL	2.5419 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.