Loading…
Structural and Physicochemical Features of Oral PROTACs
Achieving oral bioavailability with Proteolysis Targeting Chimeras (PROTACs) is a key challenge. Here, we report the in vivo pharmacokinetic properties in mouse, rat, and dog of four clinical oral PROTACs and compare with an internally derived data set. We use NMR to determine 3D molecular conformat...
Saved in:
Published in: | Journal of medicinal chemistry 2024-08, Vol.67 (15), p.13106-13116 |
---|---|
Main Authors: | , , , , , , , , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | Achieving oral bioavailability with Proteolysis Targeting Chimeras (PROTACs) is a key challenge. Here, we report the in vivo pharmacokinetic properties in mouse, rat, and dog of four clinical oral PROTACs and compare with an internally derived data set. We use NMR to determine 3D molecular conformations and structural preorganization free in solution, and we introduce the new experimental descriptors, solvent-exposed H-bond donors (eHBD), and acceptors (eHBA). We derive an upper limit of eHBD ≤ 2 for oral PROTACs in apolar environments and show a greater tolerance for other properties (eHBA, polarity, lipophilicity, and molecular weight) than for Rule-of-5 compliant oral drugs. Within a set of structurally related PROTACs, we show that examples with eHBD > 2 have much lower oral bioavailability than those that have eHBD ≤ 2. We summarize our findings as an experimental “Rule-of-oral-PROTACs” in order to assist medicinal chemists to achieve oral bioavailability in this challenging space. |
---|---|
ISSN: | 0022-2623 1520-4804 1520-4804 |
DOI: | 10.1021/acs.jmedchem.4c01017 |