Flexibility versus Rigidity for Orally Bioavailable Cyclic Hexapeptides

Cyclic peptides and macrocycles have the potential to be membrane permeable and orally bioavailable, despite often not complying with the “rule of five” used in medicinal chemistry to guide the discovery of oral drugs. Here we compare solvent‐dependent three‐dimensional structures of three cyclic hexapeptides containing d‐amino acids, prolines, and intramolecular hydrogen bonds. Conformational rigidity rather than flexibility resulted in higher membrane permeability, metabolic stability and oral bioavailability, consistent with less polar surface exposure to solvent and a reduced entropy penalty for transition between polar and nonpolar environments. Three similar cyclic peptides with varying flexibility were compared for membrane permeability, oral bioavailability and metabolic stability. We show that more rigid structures were more orally bioavailable, possibly as a result of the reduced exposure of polar surfaces and lower entropy penalty associated with crossing a membrane.