High Cell Permeability Does Not Predict Oral Bioavailability for Analogues of Cyclic Heptapeptide Sanguinamide A

Abstract

The cyclic heptapeptide derivative, sanguinamide A, is a model scaffold for studying how component amino acids, heterocycles, and N-methylation influence membrane permeability and oral bioavailability. Membrane permeable sanguinamide A analogues have been reported, but there is limited data on their pharmacokinetic properties invivo. Here we report pharmacokinetic properties for highly cell and membrane permeable sanguinamide A analogues in rats and find that there is no correlation between reported permeability invitro and oral bioavailability invivo. We show that N-methylation of sanguinamide A analogues gives compounds with greater flexibility, greater susceptibility to degradation by rat liver microsomes, and lower oral bioavailability in rats.