Syeda Shameem S, Sánchez Gladis, McDermott Jeffrey P, Cheryala Narsihmulu, Wong Henry L, Georg Gunda I, Blanco Gustavo
Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA.
Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Int J Mol Sci. 2025 Jun 12;26(12):5646. doi: 10.3390/ijms26125646.
Male contraception remains an unmet need. Na,K-ATPase α4 (NKA α4), a specific Na⁺/K⁺ transporter of the sperm flagellum, is an attractive target for male contraception. NKA α4 is critical for sperm motility and fertility, and its deletion in male mice causes complete infertility. Our previous structure-activity relationship (SAR) studies on a cardenolide scaffold identified a highly selective, safe NKAα4 inhibitor, but its complex, heavily hydroxylated structure posed challenges for modification and optimization. To address this, we employed a structural simplification strategy to synthesize novel steroidal and non-steroidal analogs and examined their effects on NKAα4 inhibition and sperm motility. Both series reduced sperm motility (up to ~50%), with IC values in the picomolar range. Compounds and displayed specificities for NKAα4 over NKAα1, did not affect sperm viability, and showed no reversibility in vitro. Notably, , featuring a hexahydronaphthalene core and a benzyltriazole moiety at C5, exhibited potent, highly selective NKAα4 inhibition, reduced sperm motility in vitro and in vivo, and blocked fertilization in vitro. This highlights as a promising lead for non-hormonal male contraception and indicates that the newly generated series of compounds possess the key characteristics needed for further development as potential non-hormonal male contraceptive agents.
男性避孕仍是一项未被满足的需求。钠钾ATP酶α4（NKA α4）是精子鞭毛的一种特定钠/钾转运蛋白，是男性避孕的一个有吸引力的靶点。NKA α4对精子活力和生育能力至关重要，在雄性小鼠中删除它会导致完全不育。我们之前对强心甾类骨架的构效关系（SAR）研究确定了一种高度选择性、安全的NKAα4抑制剂，但其复杂、高度羟基化的结构给修饰和优化带来了挑战。为了解决这个问题，我们采用了结构简化策略来合成新型甾体和非甾体类似物，并研究它们对NKAα4抑制和精子活力的影响。两个系列都降低了精子活力（高达约50%），IC值在皮摩尔范围内。化合物 和 对NKAα4的选择性高于NKAα1，不影响精子活力，并且在体外没有显示出可逆性。值得注意的是， 具有六氢萘核心和C5位的苄基三唑部分，表现出强效、高度选择性的NKAα4抑制作用，在体外和体内均降低了精子活力，并在体外阻断了受精。这突出了 作为非激素男性避孕的一个有前景的先导物，并表明新生成的一系列化合物具备作为潜在非激素男性避孕药物进一步开发所需的关键特性。
