Sulopenem etzadroxil (PF-03709270; PF 03709270) is a novel, potent and orally bioavailable ester prodrug of sulopenem, with broad-spectrum antibacterial activity against most gram-positive and gram-negative bacteria. Sulopenem etzadroxil is a penem antibiotic agent that was more stable than imipenem against swine and human dehydropeptidase-Is. Sulopenem is one of the antibiotics that do not induce the appearance of subclones resistant to the drug.

On October 25, 2024, The U.S. Food and Drug Administration has approved Orlynvah (sulopenem etzadroxil and probenecid) oral tablets for the treatment of uncomplicated urinary tract infection(s) (uUTI) caused by certain bacteria (Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis) in adult women who have limited or no alternative oral antibacterial treatment options. Orlynvah is not indicated for the primary or step-down treatment of complicated UTI (cUTI) or complicated intra-abdominal infections (cIAI). Orlynvah is taken as one oral tablet twice daily for 5 days.

Physicochemical Properties

Molecular Formula	C19H27NO7S3
Molecular Weight	477.615182161331
Exact Mass	477.094
Elemental Analysis	C, 47.78; H, 5.70; N, 2.93; O, 23.45; S, 20.14
CAS #	1000296-70-7
PubChem CID	23642298
Appearance	White to light yellow solid powder
LogP	2.1
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	10
Rotatable Bond Count	11
Heavy Atom Count	30
Complexity	767
Defined Atom Stereocenter Count	5
SMILES	CCC(CC)C(=O)OCOC(=O)C1=C(S[C@H]2N1C(=O)[C@@H]2[C@@H](C)O)S[C@H]3CC[S@@](=O)C3
InChi Key	NBPVNGWRLGHULH-JKOUTOBWSA-N
InChi Code	InChI=1S/C19H27NO7S3/c1-4-11(5-2)17(23)26-9-27-18(24)14-19(28-12-6-7-30(25)8-12)29-16-13(10(3)21)15(22)20(14)16/h10-13,16,21H,4-9H2,1-3H3/t10-,12+,13+,16-,30?/m1/s1
Chemical Name	((2-ethylbutanoyl)oxy)methyl (5R,6S)-6-((R)-1-hydroxyethyl)-3-(((3S)-1-oxidotetrahydrothiophen-3-yl)thio)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
Synonyms	PF-03709270; PF03709270; SULOPENEM ETZADROXIL; 1000296-70-7; Sulopenem etzadroxil (USAN); Sulopenem etzadroxil [USAN]; 492M3I304T; PF 03709270; PF-3709270; PF3709270; PF 3709270.
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	β-lactamase
ln Vitro	Sulopenem has _in vitro_ activity against gram-positive and gram-negative aerobic and anaerobic bacteria. The bactericidal activity of sulopenem results from the inhibition of cell wall synthesis and is mediated through sulopenem binding to penicillin binding proteins (PBPs). Sulopenem's β-lactam ring alkylates the serine residues of PBPs, ultimately inhibiting peptidoglycan cross-linking. Sulopenem, similar to other beta-lactam antibacterials, exhibits time-dependent bacterial inhibition. The percentage of time that unbound plasma concentrations of sulopenem exceed the sulopenem minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in _in vitro_ models of infection. In E. coli_, sulopenem demonstrated binding affinity for PBPs in the following order: PBP2 > PBP1A > PBP1B > PBP4 > PBP3 > PBP5/6. Sulopenem etzadroxil is a prodrug of the penem antibacterial [sulopenem]. Like other beta-lactam antibacterials, it is a time-dependent inhibitor of bacterial cell wall synthesis. Sulopenem etzadroxil was approved by the FDA in October 2024 for the treatment of uncomplicated urinary tract infections. It is administered in combination with [probenecid] in order to increase antibiotic exposure.
ln Vivo	Sulopenem etzadroxil is indicated in combination with [probenecid] for the treatment of uncomplicated urinary tract infections caused by _Escherichia coli_, _Klebsiella pneumoniae_, or _Proteus mirabilis_ in adult women who have limited or no alternative oral antibacterial treatment options. Sulopenem Etzadroxil is an orally available ester prodrug form of sulopenem, a thiopenem with broad-spectrum antibacterial activity against most gram-positive and gram-negative bacteria. After oral administration of sulopenem etzadroxil, the ester bond is cleaved, releasing active sulopenem. Sulopenem is not active against Pseudomonas aeruginosa. In addition, this agent is fairly stable against hydrolysis by various beta-lactamases.
ADME/Pharmacokinetics	Absorption Following rapid conversion into the active moiety, sulopenem bioavailability is approximately 40% in the fasted state, increasing to 64% when administered with a meal. Route of Elimination Following a single oral dose of radiolabeled sulopenem etzadroxil in healthy adult subjects, 44.3% of radioactive product was recovered in the feces (26.9% as unchanged sulopenem) and 40.8% was recovered in the urine (3.1% as unchanged sulopenem). Volume of Distribution In the fasted state, the apparent volume of distribution of sulopenem is 134 liters. When administered with a high-fat meal, the apparent volume of distribution is 92.09 liters. Clearance In the fasted state, the apparent clearance of sulopenem is 77.6 L/h. When administered with a high-fat meal, the apparent clearance is 50.55 L/h. Protein Binding Sulopenem is minimally (~11%) protein-bound in plasma. Metabolism / Metabolites After oral administration, sulopenem etzadroxil is hydrolyzed via esterases to the active [sulopenem], which is further metabolized via hydrolysis and then dehydrogenation. Two inactive metabolites of sulopenem have been identified - M1a and M1b - which accounted for 21.8% and 43.6%, respectively, of circulating radioactivity following the administration of a radiolabeled dose. Biological Half-Life In the fasted state, the mean elimination half-life of sulopenem is 1.18 hours. When administered with a high-fat meal, the mean elimination half-life is 1.28 hours.
Toxicity/Toxicokinetics	Safety Information The prescribing information includes warnings for hypersensitivity reactions, Clostridioides difficile-Associated Diarrhea (CDAD), and potential exacerbation of gout when given to patients with a known history of gout. Orlynvah is contraindicated in patients with a history of hypersensitivity reactions to the components of Orlynvah (sulopenem etzadroxil and probenecid) or other beta-lactam antibacterial drugs, patients with known blood dyscrasias, patients with known uric acid kidney stones, and patients who are also taking ketorolac tromethamine. The most common side effects of Orlynvah were diarrhea, nausea, vaginal yeast infection, headache, and vomiting.
References	[1]. Antimicrob Agents Chemother. 2009 Jun;53(6):2239-47. [2]. https://pubchem.ncbi.nlm.nih.gov/compound/23642298
Additional Infomation	Sulopenem etzadroxil is under investigation in clinical trial NCT03354598 (Oral Sulopenem-etzadroxil/probenecid Versus Ciprofloxacin for Uncomplicated Urinary Tract Infection in Adult Women). Sulopenem Etzadroxil is an orally available ester prodrug form of sulopenem, a thiopenem with broad-spectrum antibacterial activity against most gram-positive and gram-negative bacteria. After oral administration of sulopenem etzadroxil, the ester bond is cleaved, releasing active sulopenem. Sulopenem is not active against Pseudomonas aeruginosa. In addition, this agent is fairly stable against hydrolysis by various beta-lactamases. Effectiveness The effectiveness of Orlynvah was evaluated in two phase 3 controlled, randomized, double blind clinical trials (Trial 1 and Trial 2) which enrolled adult women with uUTI. Orlynvah was administered as one tablet twice daily for 5 days. Trial 1 (NCT05584657) was a noninferiority trial in which 2214 adult women with uUTI were randomized and treated. Orlynvah demonstrated efficacy in patients with amoxicillin/clavulanate-susceptible pathogens with a composite response rate (combined microbiological response and clinical response) of 62% compared to a composite response rate of 55% in the amoxicillin/clavulanate group. Trial 2 (NCT03354598) was a noninferiority trial in which 1660 adult women with uUTI were randomized and treated. Orlynvah demonstrated efficacy in patients with ciprofloxacin-resistant pathogens with a composite response rate of 48% compared to a composite response rate of 33% in the ciprofloxacin group. Overall, in the two trials combined, 1932 patients were treated with Orlynvah. Clinical trials evaluating Orlynvah for the treatment of patients with cUTI and cIAI did not demonstrate effectiveness.

Solubility Data

Solubility (In Vitro)

DMSO : ~100 mg/mL (~209.37 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.23 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 (5.23 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 (5.23 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	2.0937 mL	10.4686 mL	20.9371 mL
	5 mM	0.4187 mL	2.0937 mL	4.1874 mL
	10 mM	0.2094 mL	1.0469 mL	2.0937 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.