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

Shameem Sultana Syeda, Gladis Sánchez, Kwon Ho Hong, Jon E. Hawkinson, Gunda I. Georg, Gustavo Blanco

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

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 Ca 2+ , 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.

Original languageEnglish (US)
Pages (from-to)1800-1820
Number of pages21
JournalJournal of medicinal chemistry
Volume61
Issue number5
DOIs
StatePublished - Mar 8 2018

Bibliographical note

Funding Information:
The authors thank Dr. Rawle Francis for carrying out the hERG assay. This work was supported by the Contraception Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development through U01HD080423 (GB) and contract HHSN275201300017C (GIG). We thank NICHD program officers Dr. Diana Blithe, Dr. Daniel Johnston, and Dr. Min Lee for their support of this program.

Funding Information:
This work was supported by the Contraception Research Branch Eunice Kennedy Shriver National Institute of Child Health and Human Development through U01HD080423 (GB) and contract HHSN275201300017C (GIG). We thank NICHD program officers Dr. Diana Blithe, Dr. Daniel Johnston, and Dr. Min Lee for their support of this program.

Publisher Copyright:
© 2018 American Chemical Society.

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