Next, we evaluated SAR on the phenyl ring with lipophilic alkyl substituents. Similar to the halogen series, the ortho substituted analogs were less potent against AC1 compared to the meta and para counterparts as illustrated by a 5-fold improvement in AC1 activity when moving from the 2-methyl (15, IC50 = 2.2 µM) to the 3-methyl (16, IC50 = 0.41 µM, Table and). The improvement was more pronounced with the larger ethyl series as the 3-ethyl (20) was 7-fold more potent against AC1 than the 2-ethyl (19) derivative with IC50 values of 0.44 µM and 3.1 µM, respectively. Placing the methyl at the para-position (17) slightly reduced AC1 activity compared to the meta-methyl 16. In contrast the 4-ethyl derivative 21 was slightly more potent than the 3-ethyl nearest neighbor with an AC1 IC50 value of 0.39 µM. This series of six alkyl containing analogs appeared to be generally more selective for AC1 over AC8 (11 -28% AC8 inhibition) compared to the halogenated analogs (15 -55%). Interestingly, swapping the 3-methyl for 3-trifluoromethyl ( ) resulted in a slight reduction of AC1 activity but also reduced the selectivity over AC8 to 41%, which was a value closer to those observed for the halogenated analogs. Increasing the alkyl branching in this series provided mixed results. For example, moving from methyl (16) to ethyl (20) to iso-propyl (22) substitutions at the 3-position were essentially equipotent in terms of AC1 activity ranging from 0.36 -0.44 µM while moving to the quaternary carbon with a 3-tert-butyl modification ( ) reduced activity 2-fold to 0.88 µM. Moving the bulky tert-butyl group to the para-position (25) reduced activity further to 0.97 µM. Additionally, cyclization of the iso-propyl to cyclopropyl at the 3-position (23) resulted in more than 2-fold reduced AC1 activity at 0.88 µM compared to 0.36 µM for the iso-propyl derivative 22. The tertiary and quaternary alkyl substituent also yielded slightly reduced selectivity across the board with AC8 values ranging in the 17 -35% compared to 11 -27% for the less branched counterparts.