Aminopeptidase N (APN/CD13) is a zinc‐dependent ubiquitous transmembrane ectoenzyme that is widely present in different types of cells. APN is one of the most extensively studied metalloaminopeptidases as an anti‐cancer target due to its significant role in the regulation of metastasis and angiogenesis. Previously, we identified a potent and selective APN inhibitor, N‐(2‐(Hydroxyamino)‐2‐oxo‐1‐(3′,4′,5′‐trifluoro‐1,1′‐biphenyl‐4‐yl)ethyl)‐4‐(methylsulfonamido)benzamide (3). Herein, we report the further modifications performed to explore SAR around the S1 subsite of APN and to improve the physicochemical properties. A series of hydroxamic acid analogues were synthesised, and the pharmacological activities were evaluated in vitro. N‐(1‐(3′‐Fluoro‐1,1′‐biphenyl‐4‐yl)‐2‐(hydroxyamino)‐2‐oxoethyl)‐4‐(methylsulfonamido)benzamide (6 f) was found to display an extremely potent inhibitory activity in the sub‐nanomolar range. Targeting metastasis and angiogenesis: Hydroxamic acid bearing small molecules were synthesised as potent inhibitors of aminopeptidase N (APN) for the treatment of cancer. The 3,4,5‐trifluorophenyl group of the lead compound 3 was replaced with various substituents to improve both potency and solubility. The SAR results indicated 3‐fluorophenyl analogue 6 f to be the most potent APN inhibitor that showed inhibitory activity in the sub‐nanomolar range.