Macrocycle SAR is often more complex than the SAR of acyclic chemotypes, for example with different ring sizes resulting in distinct substituent SAR, presenting both challenges and opportunities to the medicinal chemist. By imposing different distances and relative orientations between their connection points, different linkers may restrict the orientation and freedom of motion of substituents in distinct ways, potentially leading to different SAR outcomes when these substituents are modified. The studies described above include several examples of such nonlinear SAR. Optimization of a macrocyclic inhibitor thus can require extensive empirical exploration of structure-activity space, because an SAR feature seen in one series may not translate to other, even closely related, series. This complex SAR makes it challenging to decide at what point in a discovery program to make the final choice of ring size and linker geometry. This SAR complexity also provides an opportunity, however; at any point in a discovery program where the investigators find themselves in an apparent SAR dead-end, reconsidering the linker length and geometry can potentially move the chemotype into new SAR territory that would not exist for an acyclic analog.