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Design, Synthesis, and in Vitro and in Vivo Evaluation of Ouabain Analogues as Potent and Selective Na,K-ATPase α4 Isoform Inhibitors for Male Contraception.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-19 , DOI: 10.1021/acs.jmedchem.7b00925 Shameem Sultana Syeda 1 , Gladis Sánchez 2 , Kwon Ho Hong 1 , Jon E Hawkinson 1 , Gunda I Georg 1 , Gustavo Blanco 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-19 , DOI: 10.1021/acs.jmedchem.7b00925 Shameem Sultana Syeda 1 , Gladis Sánchez 2 , Kwon Ho Hong 1 , Jon E Hawkinson 1 , Gunda I Georg 1 , Gustavo Blanco 2
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Na,K-ATPase α4 is a testis-specific plasma membrane Na+ and K+ transporter expressed in sperm flagellum. Deletion of Na,K-ATPase α4 in male mice results in complete infertility, making it an attractive target for male contraception. Na,K-ATPase α4 is characterized by a high affinity for the cardiac glycoside ouabain. With the goal of discovering selective inhibitors of the Na,K-ATPase α4 and of sperm function, ouabain derivatives were modified at the glycone (C3) and the lactone (C17) domains. Ouabagenin analogue 25, carrying a benzyltriazole moiety at C17, is a picomolar inhibitor of Na,K-ATPase α4, with an outstanding α4 isoform selectivity profile. Moreover, compound 25 decreased sperm motility in vitro and in vivo and affected sperm membrane potential, intracellular Ca2+, pH, and hypermotility. These results proved that the new ouabagenin triazole analogue is an effective and selective inhibitor of Na,K-ATPase α4 and sperm function.
中文翻译：
哇巴因类似物作为男性避孕的强效和选择性 Na,K-ATPase α4 异构体抑制剂的设计、合成以及体外和体内评价。
Na,K-ATPase α4 是一种睾丸特异性质膜 Na+ 和 K+ 转运蛋白，在精子鞭毛中表达。雄性小鼠中 Na,K-ATPase α4 的缺失导致完全不育，使其成为雄性避孕的有吸引力的目标。Na,K-ATPase α4 的特点是对强心苷哇巴因具有高亲和力。为了发现 Na,K-ATPase α4 和精子功能的选择性抑制剂，哇巴因衍生物在糖基 (C3) 和内酯 (C17) 结构域进行了修饰。Ouabagenin 类似物 25 在 C17 处带有一个苄基三唑部分，是一种皮摩尔级 Na,K-ATPase α4 抑制剂，具有出色的 α4 异构体选择性特征。此外，化合物 25 在体外和体内降低了精子活力，并影响了精子膜电位、细胞内 Ca2+、pH 和运动过度。
更新日期：2018-01-01
中文翻译：
哇巴因类似物作为男性避孕的强效和选择性 Na,K-ATPase α4 异构体抑制剂的设计、合成以及体外和体内评价。
Na,K-ATPase α4 是一种睾丸特异性质膜 Na+ 和 K+ 转运蛋白，在精子鞭毛中表达。雄性小鼠中 Na,K-ATPase α4 的缺失导致完全不育，使其成为雄性避孕的有吸引力的目标。Na,K-ATPase α4 的特点是对强心苷哇巴因具有高亲和力。为了发现 Na,K-ATPase α4 和精子功能的选择性抑制剂，哇巴因衍生物在糖基 (C3) 和内酯 (C17) 结构域进行了修饰。Ouabagenin 类似物 25 在 C17 处带有一个苄基三唑部分，是一种皮摩尔级 Na,K-ATPase α4 抑制剂，具有出色的 α4 异构体选择性特征。此外，化合物 25 在体外和体内降低了精子活力，并影响了精子膜电位、细胞内 Ca2+、pH 和运动过度。
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