Highly Potent and Subtype-Selective Sperm-Specific Potassium Channel SLO3 Inhibitors Display High Tissue Exposure in the Murine Female Reproductive Tract
To date, the study of drug exposure and distribution throughout the female reproductive tract has often been overlooked and neglected. Herein, we report the first highly potent and subtype-selective sperm-specific potassium channel 3 (SLO3) inhibitors as a new modality of contraceptives. After extensive <i>in vitro</i> and <i>in vivo</i> drug metabolism and pharmacokinetic profiling we selected <b>VU6032735</b> to utilize as a tool compound. <b>VU6032735</b> displayed low observed clearance with a long half-life and a high volume of distribution in female mice, which is seemingly an ideal target profile for a nonhormonal contraceptive. After intraperitoneal injection, we evaluated the drug exposure and distribution throughout various compartments of the murine female reproductive tract. Over a 24-h time course, <b>VU6032735</b> sustained high tissue exposure in the oviduct, where fertilization takes place. This work provides the framework for others interested in studying drug exposure and distribution throughout the female reproductive tract.
Authors
- Kayla J. Temple (ORCID: https://orcid.org/0000-0001-5290-574X)
- Jeremy A. Turkett
- Katherine J. Watson
- Valerie M. Kramlinger (ORCID: https://orcid.org/0000-0002-7237-164X)
- Ronald McCarthy (ORCID: https://orcid.org/0000-0001-5942-5968)
- Irene A. Zagol-Ikapitte
- Maximilian D. Lyon (ORCID: https://orcid.org/0000-0002-2930-1726)
- Jerod S. Denton (ORCID: https://orcid.org/0000-0003-0032-8586)
- Shweta Bhagwat (ORCID: https://orcid.org/0000-0003-2278-3264)
- Celia Maria Santi (ORCID: https://orcid.org/0000-0002-5101-1303)
- Carrie K. Jones (ORCID: https://orcid.org/0000-0002-1287-9839)
- Analisa Thompson Gray
- Craig W. Lindsley (ORCID: https://orcid.org/0000-0003-0168-1445)
- Roman M. Lazarenko (ORCID: https://orcid.org/0000-0003-0177-2961)
- Olivier G. Boutaud (ORCID: https://orcid.org/0000-0002-8910-0598)
- Jeanette L. Bertron (ORCID: https://orcid.org/0000-0002-3743-692X)
- Patricia Van Horn
- Anna E. Ringuette
- Leila Asadi (ORCID: https://orcid.org/0000-0001-6896-519X)
- Ping Li (ORCID: https://orcid.org/0000-0003-2827-6925)
- Sophia Li
- Sichen Chang
- Hallie G. McKinnie
Institutions
- Allen Institute for Brain Science (US)
- Vanderbilt University (US)
- Washington University in St. Louis (US)
- Institute of Chemical Biology and Fundamental Medicine (RU)
- Center for Discovery (US)
- Vanderbilt Health (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- ACS Pharmacology & Translational Science
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1021/acsptsci.5c00416
- Primary Topic
- Reproductive Health and Contraception
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Bill and Melinda Gates Foundation
- William K. Warren Foundation
- Eunice Kennedy Shriver National Institute of Child Health and Human Development