A cell-based high-throughput screen identified the pyrazolo-pyrimidine scaffold with inhibitory activity against Ca 2+ /CaM-stimulated AC1 cAMP production. A ligand-based SAR optimization campaign, with 36 novel analogs, explored modifications to the benzamide portion of the scaffold to improve AC1 inhibitory activity and improve selectivity over the closely related AC8. It was observed that hydrophobic substitutions on the phenyl ring at both the metaand para-positions provided IC50 values as low as 0.25 µM with reduced activity against AC8.