Optimizing PK properties of cyclic peptides: the effect of side chain substitutions on permeability and clearance

Abstract

A series of cyclic peptides were designed and prepared to investigate the physicochemical properties that affect oral bioavailabilty of this chemotype in rats. In particular, the ionization state of the peptide was examined by the incorporation of naturally occurring amino acid residues that are charged in differing regions of the gut. In addition, data was generated in a variety of in vitro assays and the usefulness of this data in predicting the subsequent oral bioavailability observed in the rat is discussed.

Cyclic Penta- and Hexaleucine Peptides without N-Methylation Are Orally Absorbed

“…10,11 Membrane permeability is often used to predict whether a compound will be orally absorbed since the first barrier after surviving the GI tract is membrane permeation and resistance to enterocyte metabolism. 22−25 In the RRCK assay, compound 1 had lower permeability (P app = 1.7 × 10 −6 cm·s −1 ) than CSA (P app = 5 × 10 −6 cm·s −1 ), 12 while cyclic hexapeptide isomers 2 and 3 had 6−7-fold greater permeability than 1 and 2−3-fold higher RRCK permeability than CSA ( Figure 1A).…”

Predicting the unpredictable: Recent structure–activity studies on peptide-based macrocycles

“…In summary, these results support the conclusions from the San A studies, where a single N-methyl or D-amino acid can modify the 3-D conformation of the macrocycle thereby impacting its biological activity, however, making general sweeping statements or observing significant trends is not possible. Furthermore, these data show that contrary to currently held beliefs [43][44][45][46][47][48][50][51][52] that macrocycles can be improved as drugs with specific modifications, their biological activity can only be obtained on a trial and error basis. Fig.…”

Optimizing the Permeability and Oral Bioavailability of Macrocycles

“…23,40,49 The conformational sampling of macrocycles is significantly more challenging than for Rule-of-5 compliant small molecules. The larger size and greater number of rotatable bonds typically observed for macrocycles is one obvious reason.…”