Gepotidacin

Gepotidacin

CAS

WeightAverage: 448.527
Monoisotopic: 448.222288786 Chemical FormulaC₂₄H₂₈N₆O₃
(3R)-3-({4-[({2H,3H,4H-pyrano[2,3-c]pyridin-6-yl}methyl)amino]piperidin-1-yl}methyl)-1,4,7-triazatricyclo[6.3.1.0^{4,12}]dodeca-6,8(12),9-triene-5,11-dione

FDA APPROVED 3/25/2025,Blujepa, To treat uncomplicated urinary tract infections

Gepotidacin, sold under the brand name Blujepa, is an antibiotic medication used for the treatment of urinary tract infection.^[1] Gepotidacin is a triazaacenaphthylene bacterial type II topoisomerase inhibitor.^[1][2] It is used as the salt gepotidacin mesylate, and is taken by mouth.^[1]

Gepotidacin was approved for medical use in the United States in March 2025.^[1][3]

SYNTHESIS

 Gepotidacin

Gepotidacin (GSK2140944) is a triazaacenaphtylene developed by GSK and belongs to the class of Novel Bacterial Topoisomerase Inhibitors (NBTI). This new antibiotic is currently being investigated in three phase 3 clinical trials.

Gepotidacin is derived from the analogue GSK299423 described by Bax et al. [9], which results from a medicinal chemistry program initiated after an unbiased antibacterial screening [10].

2.2.1 Chemical synthesis

The synthesis of gepotidacin has been described in two patents in 2008 and 2016 and comprises 11 steps (Fig. 2) [11,12]. First, 2-chloro-6-methoxy-3-nitro-pyridine reacts with 2-amino-propane-1,3-diol through nucleophilic aromatic substitution (S_NAr). The resulting diol is then protected with 2,2-dimethoxypropane in presence of p-toluenesulfonic acid (PTSA) followed by the reduction of the nitro group with hydrogen and 10% Pd/C. The aniline thus formed is then alkylated with ethyl bromoacetate. Cyclization is performed in basic conditions using sodium hydride, followed by oxidation using manganese dioxide. The acetal is then cleaved and the released diol reacts with methanesulfonic anhydride to form the third cycle of the triazaacenaphtylene core. Substitution with Boc-amino-piperidine, followed by deprotection and subsequent purification by chiral chromatography affords the primary amine derivative, which can be condensed by reductive amination with the corresponding aldehyde to give the free base of gepotidacin. The mono-hydrochloride salt is obtained by reaction with one equivalent of HCl 1 M in diethylether [13].

PATENT

WO2021219637A1

https://patents.google.com/patent/WO2021219637A1/en

Gepotidacin mesylate dihydrate (Form 1)

Example la – Preparation Method 1

Acetone (5 ml) was added to gepotidacin (294.14 mg). To the slurry, methanesulfonic acid (3M solution in water, 1 equivalent) was added over a period of 60 minutes. The slurry was heated to 50°C for 3 hours, cooled slowly to 20°C, left stirring at 20°C for 5 hours and cooled further to 5°C. The slurry was stirred at 5°C overnight. The crystalline solids were filtered under vacuum, washed with acetone and dried in a vacuum oven at 60°C to give crystalline gepotidacin mesylate dihydrate (Form 1) in 72.9% yield.

WO2008128942A1

References:

GLAXO GROUP LIMITED WO2008/128942, 2008, A1Yield:-

Steps:

Multi-step reaction with 12 steps
1.1: ethanol; water / 4 h / 0 °C / Heating / reflux
2.1: toluene-4-sulfonic acid / 20 °C
2.2: 0.33 h
3.1: hydrogen / palladium 10% on activated carbon / 1,4-dioxane / 20 °C / 760.05 Torr
4.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C
5.1: sodium hydride / tetrahydrofuran / 3.25 h / 0 – 20 °C
6.1: manganese(IV) oxide / dichloromethane / 2 h / 20 °C
7.1: hydrogenchloride; water / tetrahydrofuran / 1 h / 20 °C
7.2: pH ~ 8
8.1: triethylamine / chloroform / 4.5 h / Heating / reflux
9.1: pyridine / acetonitrile / 5 h / 50 – 90 °C
10.1: hydrogenchloride / 1,4-dioxane; dichloromethane / 1 h / 20 °C
11.1: isopropylamine / methanol; acetonitrile / Resolution of racemate
12.1: methanol; chloroform / 20 °C
12.2: 0.5 h / 20 °C

Example 10 (lR)-l-({4-[(3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-ylmethyl)amino]- l-piperidinyl}methyl)-l,2-dihydro-4H,9H-imidazo[l,2,3-//]-l,8-naphthyridine-4,9- dione hydrochloride

A suspension of (\R)- 1 -[(4-amino- 1 -piperidinyl)methyl]- 1 ,2-dihydro-4Η,9Η- imidazo[l,2,3-ij]-l,8-naphthyridine-4,9-dione (for a preparation see Example 5(j)) (51 mg, 0.14 mmol) in chloroform:methanol (9:1, 3 ml) at rt under argon was treated with triethylamine (0.06ml) and stirred at rt for 10 min. The solution was then treated with 1,3- dihydrofuro[3,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144,

Example 126(e)) (21mg, 0.133mmol) and stirred for a further 2h. The solution was then treated with NaBH(OAc)₃ (87mg) and stirred at rt for 2h. The reaction was then treated with saturated aqueous NaHCO (10ml) and extracted with 20% methanol/DCM (3 x 50ml). The combined organic extracts were dried (MgSO ), filtered, evaporated and chromatographed (0-20% methanol/DCM) to give the free base of the title compound as a light brown solid (20mg, 32%) MS (ES+) m/z 448 (MH⁺). δH (CDCl₃, 400MHz) 1.15-1.49 (2H, m), 1.61-1.95 (2H, m), 1.99-2.09 (2H, m) 2.20-2.38 (IH, m), 2.45-2.85 (6H, m), 2.92-3.02(1H, m), 3.05-3.15 (IH, m), 3.78 (2H, s), 4.20 (2H, t), 4.30-4.42 (IH, m), 4.52-4.61 (IH, m), 4.95-5.05 (IH, m), 6.23-6.32 (2H, m), 7.00 (IH, s), 7.47-7.50 (2H, m), 8.07 (IH, s).

The free base in DCM was treated with one equivalent IM HCl in diethyl ether and then evaporated to give the title monohydrochloride salt.

WO2016027249A1

PATENT

WO2004058144

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2004058144&_cid=P20-M9AS9E-95245-1

Medical uses

Gepotidacin is indicated for the treatment of females aged twelve years of age and older weighing at least 40 kilograms (88 lb) with uncomplicated urinary tract infections (uUTI) caused by Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii complex, Staphylococcus saprophyticus, and Enterococcus faecalis.^[1]

Society and culture

Legal status

In October 2024, gepotidacin was granted priority review by the US Food and Drug Administration (FDA) for the treatment of uncomplicated urinary tract infections.^[4]

Gepotidacin was approved for medical use in the United States in March 2025.^[1][5]

Names

Gepotidacin is the international nonproprietary name.^[6]

Gepotidacin is sold under the brand name Blujepa.^[1][5]

Research

Gepotidacin is being studied for the treatment of Neisseria gonorrhoeae (gonorrhea) infection, including multidrug resistant strains.^[7][8]

References

1. ^ Jump up to:^{a b c d e f g h} “Blujepa- gepotidacin tablet, film coated”. DailyMed. 25 March 2025. Retrieved 2 April 2025.
2. ^ Biedenbach DJ, Bouchillon SK, Hackel M, Miller LA, Scangarella-Oman NE, Jakielaszek C, et al. (January 2016). “In Vitro Activity of Gepotidacin, a Novel Triazaacenaphthylene Bacterial Topoisomerase Inhibitor, against a Broad Spectrum of Bacterial Pathogens”. Antimicrobial Agents and Chemotherapy. 60 (3): 1918–1923. doi:10.1128/aac.02820-15. PMC 4776004. PMID 26729499.
3. ^ Fick M, Sneha SK, Sunny ME (2025). “FDA approval”. Reuters.
4. ^ “GSK’s investigational antibiotic granted FDA priority review for urinary tract infections”. PMLiVE. 18 October 2024. Retrieved 21 October 2024.
5. ^ Jump up to:^a b “Blujepa (gepotidacin) approved by US FDA for treatment of uncomplicated urinary tract infections (uUTIs) in female adults and pediatric patients 12 years of age and older”. GSK (Press release). 25 March 2025. Retrieved 28 March 2025.
6. ^ World Health Organization (2015). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 74”. WHO Drug Information. 29 (3). hdl:10665/331070.
7. ^ Scangarella-Oman NE, Hossain M, Dixon PB, Ingraham K, Min S, Tiffany CA, et al. (December 2018). “Microbiological Analysis from a Phase 2 Randomized Study in Adults Evaluating Single Oral Doses of Gepotidacin in the Treatment of Uncomplicated Urogenital Gonorrhea Caused by Neisseria gonorrhoeae“. Antimicrobial Agents and Chemotherapy. 62 (12). doi:10.1128/AAC.01221-18. PMC 6256812. PMID 30249694.
8. ^ Jacobsson S, Golparian D, Scangarella-Oman N, Unemo M (August 2018). “In vitro activity of the novel triazaacenaphthylene gepotidacin (GSK2140944) against MDR Neisseria gonorrhoeae“. The Journal of Antimicrobial Chemotherapy. 73 (8): 2072–2077. doi:10.1093/jac/dky162. PMC 6927889. PMID 29796611.

Further reading

• Wagenlehner F, Perry CR, Hooton TM, Scangarella-Oman NE, Millns H, Powell M, et al. (February 2024). “Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials”. Lancet. 403 (10428): 741–755. doi:10.1016/S0140-6736(23)02196-7. PMID 38342126. S2CID 267548740.

External links

• Clinical trial number NCT04020341 for “A Study to Evaluate Efficacy and Safety of Gepotidacin in the Treatment of Uncomplicated Urinary Tract Infection (UTI)” at ClinicalTrials.gov
• Clinical trial number NCT04187144 for “Comparative Study to Evaluate Efficacy and Safety of Gepotidacin to Nitrofurantoin in Treatment of Uncomplicated Urinary Tract Infection (UTI)” at ClinicalTrials.gov

1. Ross JE, Scangarella-Oman NE, Flamm RK, Jones RN: Determination of disk diffusion and MIC quality control guidelines for GSK2140944, a novel bacterial type II topoisomerase inhibitor antimicrobial agent. J Clin Microbiol. 2014 Jul;52(7):2629-32. doi: 10.1128/JCM.00656-14. Epub 2014 Apr 23. [Article]
2. Oviatt AA, Gibson EG, Huang J, Mattern K, Neuman KC, Chan PF, Osheroff N: Interactions between Gepotidacin and Escherichia coli Gyrase and Topoisomerase IV: Genetic and Biochemical Evidence for Well-Balanced Dual-Targeting. ACS Infect Dis. 2024 Apr 12;10(4):1137-1151. doi: 10.1021/acsinfecdis.3c00346. Epub 2024 Mar 5. [Article]
3. GSK Press Release: Blujepa (gepotidacin) approved by US FDA for treatment of uncomplicated urinary tract infections (uUTIs) in female adults and paediatric patients 12 years of age and older [Link]
4. FDA Approved Drug Products: Blujepa (gepotidacin) tablets for oral use (March 2025) [Link]

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