The urotensin-II (U-II) receptor is as a G-protein coupled receptor (GPCR) that is activated by a small cyclic peptide, U-II (e.g., AGTADCFWKYCV). The agonist peptide was first isolated from the goby fish, and found to possess potent vasoconstrictor activity in fish and mammals. In addition, U-II is thought to be involved in the development of acute and chronic renal failure, congestive heart failure, and diabetes. Evaluation of derivatives of goby U-II in a rat U-II functional assay (FLIPR) identified the key three-point pharmacophore W-K-Y, which is essential for receptor activation. A phenyl piperidine based antagonist was identified via HTS and it was optimized and elaborated using Suzuki-Miyaura cross coupling methodology. To explore this strategy a variety of aryl halides were connected to heterocyclic vinyl boronates. The synthesis and SAR will be discussed from HTS hit to lead identification