As selectivity is a critical parameter for AC1 inhibitors to be considered for clinical use, we examined the activity profile of the pyrimidinone scaffold for potency against other AC isoforms (Figure , Table ). Screening versus representative Group I, II, and III AC isoforms showed partial inhibition of Ca 2+ /CaM-stimulated AC8 activity, weak potentiation of Phorbol 12myristate 13 acetate (PMA)-stimulated AC2 activity, and no apparent effect on forskolinstimulated AC5 activity (Figure ). This data supports that the scaffold is selective for AC1 against not only the Ca 2+ /CaM-stimulated AC8 but also against AC isoforms that are differentially activated.