Discovery of Potent and Orally Bioavailable Macrocyclic Peptide–Peptoid Hybrid CXCR7 Modulators

The chemokine receptor CXCR7 is an
attractive target for a variety
of diseases. While several small-molecule modulators of CXCR7 have
been reported, peptidic macrocycles may provide advantages in terms
of potency, selectivity, and reduced off-target activity. We produced
a series of peptidic macrocycles that incorporate an N-linked peptoid
functionality where the peptoid group enabled us to explore side-chain
diversity well beyond that of natural amino acids. At the same time,
theoretical calculations and experimental assays were used to track
and reduce the polarity while closely monitoring the physicochemical
properties. This strategy led to the discovery of macrocyclic peptide–peptoid
hybrids with high CXCR7 binding affinities (Ki < 100 nM) and measurable passive permeability (Papp > 5 × 10–6 cm/s).
Moreover, bioactive peptide 25 (Ki = 9 nM) achieved oral bioavailability of 18% in rats, which
was commensurate with the observed plasma clearance values upon intravenous
administration.