The apelin receptor (APJ) has emerged as a potential novel therapeutic target in cancer due to its role in regulating cell proliferation, angiogenesis, and metastasis. However, ML221, the only known selective small molecule APJ antagonist, exhibits poor plasma and liver microsomal stability, limiting its in vivo applicability. To overcome these limitations, a focused medicinal chemistry effort was undertaken to design and synthesize a second-generation series of APJ antagonists with improved metabolic stability while retaining APJ antagonist activity. Structure–activity relationship analysis identified compound 12 (YL-GB063) as the most favorable analog, displaying enhanced liver microsomal stability relative to lead compounds 6 (YL-GB053) and 7 (YL-GB054), while maintaining APJ inhibition. Pharmacokinetic evaluation revealed a >25-fold increase in systemic exposure compared to ML221. In an orthotopic ovarian cancer xenograft mouse model, YL-GB063 significantly increased median survival and reduced metastatic tumor burden and ascites formation compared to both control and ML221-treated groups.