However, in compound pair 32/33, which differ from 30/31 only in the absence of two methyl groups, the same one-atom increase in linker length resulted in a >16-fold increase in potency against the same target (Figure ). This result highlights that SAR for macrocyclic chemotypes can be significantly nonlinear, such that the effect of a structural change in one compound series can be strikingly different from those seen in another closely related series.