However, during the design we were also cognizant of modifications that may improve solubility and/or BBB permeability. After SAR optimization of the benzamide moiety, we were able to improve potency by 2 -4-fold across the series of analogs versus Ca 2+ /CaM-stimulated AC1 activity while maintaining/improving selectivity versus AC8. The SAR revealed a 6-membered aromatic group was preferred on the amide as both the phenyl and 2-pyridine functional groups were comparable with low-micromolar potency against AC1. We moved forward with phenyl modifications for two reasons: 1) a greater availability of substituted reagents to better explore SAR and 2) we wanted to limit the number of heteroatoms in an attempt to improve BBB permeability. Hydrophobic substituents were preferred on the phenyl ring, particularly at the metaor para-positions. Furthermore, the potent activity of analogs 26 (3-phenyl) and 27 (4-phenyl) implies a larger capacity or perhaps flexibility of the putative molecule binding site to accommodate flat hydrophobic substitutions. While the increased lipophilicity is generally helpful to improve BBB permeability it is typically is detrimental to solubility. A few analogs that incorporated polar functional groups such as methoxy, hydroxy, and dimethyl amino all resulted in reduced potency against AC1 activity compared to the top leads.