Following our previous reports of selective AC1 inhibitors for chronic pain, we sought to discover a scaffold with improved drug-like characteristics and potency while maintaining selectivity versus AC8. The same high-throughput screen that identified the prior oxadiazole series also yielded the pyrazolyl-pyrimidinone scaffold as potent AC1 inhibitors with selectivity against AC8 and having higher predicted aqueous solubility. The optimization was multifaceted as we sought to improve AC1 potency while maintaining/improving selectivity over AC8.