Optimization of Ethoxzolamide Analogs with Improved Pharmacokinetic Properties for In Vivo Efficacy against Neisseria gonorrhoeae,Journal of Medicinal Chemistry

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Optimization of Ethoxzolamide Analogs with Improved Pharmacokinetic Properties for In Vivo Efficacy against Neisseria gonorrhoeae
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-14 , DOI: 10.1021/acs.jmedchem.4c01187
Molly S Youse ₁ , Nader S Abutaleb _{2,

3} , Alessio Nocentini ₄ , Abdallah S Abdelsattar _{2,

3} , Farman Ali ₁ , Claudiu T Supuran ₄ , Mohamed N Seleem _{2,

3} , Daniel P Flaherty _{1,

5,

6}

Affiliation

Drug-resistant gonorrhea is caused by the bacterial pathogen Neisseria gonorrhoeae, for which there is no recommended oral treatment. We have demonstrated that the FDA-approved human carbonic anhydrase inhibitor ethoxzolamide potently inhibits N. gonorrhoeae; however, is not effective at reducing N. gonorrhoeae bioburden in a mouse model. Thus, we sought to optimize the pharmacokinetic properties of the ethoxzolamide scaffold. These efforts resulted in analogs with improved activity against N. gonorrhoeae, increased metabolic stability in mouse liver microsomes, and improved Caco-2 permeability compared to ethoxzolamide. Improvement in these properties resulted in increased plasma exposure in vivo after oral dosing. Top compounds were investigated for in vivo efficacy in a vaginal mouse model of gonococcal genital tract infection, and they significantly decreased the gonococcal burden compared to vehicle and ethoxzolamide controls. Altogether, results from this study provide evidence that ethoxzolamide-based compounds have the potential to be effective oral therapeutics against gonococcal infection.

中文翻译：

优化乙恶佐胺类似物的药代动力学特性，以提高体内抗淋病奈瑟菌的功效

耐药性淋病是由细菌病原体淋病奈瑟菌引起的，目前没有推荐的口服治疗方法。我们已经证明 FDA 批准的人碳酸酐酶抑制剂乙氧唑酰胺可有效抑制淋病奈瑟菌；然而，它不能有效减少小鼠模型中淋病奈瑟菌的生物负载。因此，我们试图优化乙氧唑酰胺支架的药代动力学特性。与乙氧唑胺相比，这些努力导致类似物具有改善的抗淋病奈瑟菌活性、增加的小鼠肝微粒体代谢稳定性以及改善的 Caco-2 渗透性。这些特性的改善导致口服给药后体内血浆暴露量增加。研究了顶级化合物在淋球菌生殖道感染阴道小鼠模型中的体内功效，与载体和乙恶唑胺对照相比，它们显着降低了淋球菌负担。总而言之，这项研究的结果提供了证据，表明基于乙氧唑酰胺的化合物有可能成为有效的口服治疗淋菌感染的药物。

更新日期：2024-08-14

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