Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 5, Pages 1800-1820Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00925
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- Contraception Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01HD080423, HHSN275201300017C]
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Na,K-ATPase alpha 4 is a testis-specific plasma membrane Na+ and K+ transporter expressed in sperm flagellum. Deletion of Na,K-ATPase alpha 4 in male mice results in complete infertility, making it an attractive target for male contraception. Na,K-ATPase alpha 4 is characterized by a high affinity for the cardiac glycoside ouabain. With the goal of discovering selective inhibitors of the Na,K-ATPase alpha 4 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 alpha 4, with an outstanding alpha 4 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 alpha 4 and sperm function.
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