Extensive additional structural modification of this and a related scaffold resulted in a number of other compounds with low nanomolar potency. All of the most potent compounds contained rings that were from one to six atoms larger than the 14-membered ring present in consistent with the notion that constraints on ring flexibility were responsible for the poor binding of this compound. Notably, no compound was identified that had greater potency than the acyclic 12. This example illustrates how macrocyclization can lock a compound into a conformation that has the entropic benefits of preorganization, but nevertheless gains little or no affinity because it is constrained in a non-ideal geometry that brings enthalpic liabilities such as strain or misaligned interactions.