{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T10:08:40Z","timestamp":1782122920449,"version":"3.54.5"},"reference-count":45,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01HD102623"],"award-info":[{"award-number":["R01HD102623"]}]},{"name":"NIH","award":["HHSN275201300017C"],"award-info":[{"award-number":["HHSN275201300017C"]}]},{"name":"NICHD","award":["R01HD102623"],"award-info":[{"award-number":["R01HD102623"]}]},{"name":"NICHD","award":["HHSN275201300017C"],"award-info":[{"award-number":["HHSN275201300017C"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Male contraception remains an unmet need. Na,K-ATPase \u03b14 (NKA \u03b14), a specific Na\u207a\/K\u207a transporter of the sperm flagellum, is an attractive target for male contraception. NKA \u03b14 is critical for sperm motility and fertility, and its deletion in male mice causes complete infertility. Our previous structure\u2013activity relationship (SAR) studies on a cardenolide scaffold identified a highly selective, safe NKA\u03b14 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 NKA\u03b14 inhibition and sperm motility. Both series reduced sperm motility (up to ~50%), with IC50 values in the picomolar range. Compounds 13 and 45 displayed specificities for NKA\u03b14 over NKA\u03b11, did not affect sperm viability, and showed no reversibility in vitro. Notably, 45, featuring a hexahydronaphthalene core and a benzyltriazole moiety at C5, exhibited potent, highly selective NKA\u03b14 inhibition, reduced sperm motility in vitro and in vivo, and blocked fertilization in vitro. This highlights 45 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.<\/jats:p>","DOI":"10.3390\/ijms26125646","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T11:47:07Z","timestamp":1749728827000},"page":"5646","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Strategies to Develop Na,K-ATPase-\u03b14 Inhibitors as Male Contraceptives"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6986-1819","authenticated-orcid":false,"given":"Shameem S.","family":"Syeda","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gladis","family":"S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3566-3483","authenticated-orcid":false,"given":"Jeffrey P.","family":"McDermott","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narsihmulu","family":"Cheryala","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1755-1485","authenticated-orcid":false,"given":"Henry L.","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8900-9460","authenticated-orcid":false,"given":"Gunda I.","family":"Georg","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7721-9869","authenticated-orcid":false,"given":"Gustavo","family":"Blanco","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,12]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Isozymes and the regulatory structure of the genome","volume":"14","author":"Markert","year":"1987","journal-title":"Isozymes Curr. 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