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J Med Chem. 2017 Mar 9;60(5):1665-1672. doi: 10.1021/acs.jmedchem.6b01483. Epub 2017 Jan 25.

Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules.

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Department of Chemistry and Biochemistry, University of California , Santa Cruz, California 95064, United States.
World Wide Medicinal Chemistry, Groton Laboratories, Pfizer Inc. , Groton, Connecticut 06340, United States.
Modality Research Laboratories, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
World Wide Medicinal Chemistry, Cambridge Laboratories, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.


Macrocyclic peptides are considered large enough to inhibit "undruggable" targets, but the design of passively cell-permeable molecules in this space remains a challenge due to the poorly understood role of molecular size on passive membrane permeability. Using split-pool combinatorial synthesis, we constructed a library of cyclic, per-N-methlyated peptides spanning a wide range of calculated lipohilicities (0 < AlogP < 8) and molecular weights (∼800 Da < MW < ∼1200 Da). Analysis by the parallel artificial membrane permeability assay revealed a steep drop-off in apparent passive permeability with increasing size in stark disagreement with current permeation models. This observation, corroborated by a set of natural products, helps define criteria for achieving permeability in larger molecular size regimes and suggests an operational cutoff, beyond which passive permeability is constrained by a sharply increasing penalty on membrane permeation.

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