Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, United States.
J Med Chem. 2024 Sep 12;67(17):15537-15556. doi: 10.1021/acs.jmedchem.4c01187. Epub 2024 Aug 14.
Drug-resistant gonorrhea is caused by the bacterial pathogen , for which there is no recommended oral treatment. We have demonstrated that the FDA-approved human carbonic anhydrase inhibitor ethoxzolamide potently inhibits ; however, is not effective at reducing 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 , increased metabolic stability in mouse liver microsomes, and improved Caco-2 permeability compared to ethoxzolamide. Improvement in these properties resulted in increased plasma exposure after oral dosing. Top compounds were investigated for 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.
耐抗生素淋病是由细菌性病原体引起的，目前尚无推荐的口服治疗方法。我们已经证明，美国食品和药物管理局批准的人碳酸酐酶抑制剂乙氧唑胺能够有效抑制 ，但在减少 小鼠模型中的生物负荷方面效果不佳。因此，我们试图优化乙氧唑胺骨架的药代动力学特性。这些努力产生了比乙氧唑胺活性更高的类似物，在小鼠肝微粒体中的代谢稳定性提高，与乙氧唑胺相比，Caco-2 通透性提高。这些特性的改善导致口服给药后血浆暴露增加。对这些化合物在阴道小鼠淋病生殖道感染模型中的疗效进行了研究，与载体和乙氧唑胺对照组相比，它们显著降低了淋病奈瑟菌的负荷。总之，这项研究的结果提供了证据，证明基于乙氧唑胺的化合物有可能成为治疗淋病奈瑟菌感染的有效口服疗法。
