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J Med Chem. 2017 Dec 14;60(23):9653-9663. doi: 10.1021/acs.jmedchem.7b01028. Epub 2017 Oct 30.

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

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Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.
Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
Department of Pharmaceutical Chemistry, University of California , San Francisco, California 94158, United States.
Circle Pharma , South San Francisco, California 94080, United States.


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.

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