Building upon our previous work, we identified a pyrimidinone scaffold of AC1 modulators from the same high-throughput screen used to discover the oxadiazole series. These pyrimidinone AC1 modulators, represented by hit 1, displayed similar potency as ST034307 and AC10065 while maintaining selectivity versus AC8. After resynthesizing and validating these hits, they were found to be potent and selective for inhibiting Ca 2+ /CaM-stimulated AC1 activity over AC8, with maximal inhibition versus AC8 of 25-50% at the highest concentrations tested. Our team then designed and synthesized the following series of pyrimidinone analogs to elucidate the SAR, improve potency versus AC1, and maintain selectivity. Following activity testing a prioritized analog was chosen for in vivo testing in the behavioral CFA-inflammatory pain model. Our results detailing the discovery of a sub-micromolar inhibitor of AC1-mediated Ca 2+ /CaM cAMP production with selectivity versus AC8 and other AC isoforms are described below.