In the first cohort we examined the effects of fluorine, chlorine, and bromine on compound activity. No change in activity was observed moving from 2-F in 1 to 3-F in analog 10. However, moving the fluorine to the para-position (11) provided roughly 2-fold improvement in AC1 potency an IC50 value of 0.79 µM while the AC8 activity was relatively unchanged. Substitution for chlorine at either the meta- (12) or para-position (13) yielded modest 2-to 3-fold improvement of potency compared to the fluorine containing counterparts with AC1 IC50 values of 0.47 and 0.37 µM, respectively. No improvement in selectivity versus AC8 was observed as the analogs still remained around 50% inhibition at the AC1 IC90 value. The 3-Br analog (14) displayed slightly reduced potency toward AC1 (IC50 value of 0.61 µM) compared to the corresponding 3-Cl, however, this analog showed the first boost in selectivity over AC8 with only 15% inhibition of the isoform. Attempts were made to synthesize analogs with chlorine or bromine at the ortho position, however yields were very low for these reactions and did not provide enough material for testing. a Indicated groups were benzene ring replacements. b AC1 IC50s calculated from concentration-response curves with inhibitor versus 3 µM A23187-stimulated cAMP accumulation in HEK AC1 3/6 KO cell lines (n=3+). c AC1 IC90s were calculated from AC1 concentration-response curves and then interpolated through AC8 concentration-response curves (n=2+) and subtracted from 100%. All tabular AC1 IC90 data is provided in Table . ND = not determined by Prism software due to wide variance or not enough data points at higher concentrations.