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.

Fig. 1

log D vs. RRCK plot. The R² is shown excluding and including the outliers, compounds 8 and 12, which had poor recoveries.

Fig. 2

log D vs. log HLM plot. The R² correlation excludes censored measurements (<8 mL min⁻¹ kg⁻¹ and >300 mL min⁻¹ kg⁻¹).

Fig. 3

Computational workflow.

Fig. 4

Linear regression model between in vitro cell permeability measurements and in silico permeability predictions. Outliers excluded from the regression analysis (8 and 12) are in grey squares.

Fig. 5

Predicted membranephilic conformation of 3.

Scheme 1

On-resin conversion of Asp(OMe) to the tertiary amine in compounds 13 and 15.