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 in vitro and in vivo drug metabolism and pharmacokinetic profiling we selected VU6032735 to utilize as a tool compound. VU6032735 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, VU6032735 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.