Inhibition of BACE1, an enzyme involved in amyloid production, has been extensively investigated as a potential treatment for Alzheimer's disease. BACE1 inhibitors must possess very precise physicochemical properties to pass through the blood-brain barrier: while cyclic amidines have been demonstrated to be potent BACE1 inhibitors, substantial reduction of amidine basicity is necessary to achieve suitable brain penetration. In 2013, Rombouts and co-workers at Janssen investigated the effect of electron-withdrawing groups on the basicity of tricyclic amidine BACE1 inhibitors. We modeled this dataset with Rowan pKa: while some compounds were modeled quite accurately, Rowan overestimated the effect that an αnitrile substituent would have on lowering amidine basicity, resulting in large deviations from experiment (Figure ). Nevertheless, the error induced by an α-nitrile is systematic, allowing for comparisons to be made between different nitrile-containing compounds. Exp. pKa: 6.0 Pred. pKa: 4.59