AI Article Synopsis
- Achieving oral bioavailability in Proteolysis Targeting Chimeras (PROTACs) is difficult, and this study examines the pharmacokinetic properties of four oral PROTACs in mice, rats, and dogs.
- Using NMR, the researchers analyzed the 3D structures of these compounds and introduced two new experimental descriptors, solvent-exposed hydrogen bond donors (eHBD) and acceptors (eHBA).
- The findings highlight that oral PROTACs with eHBD values greater than 2 have significantly lower bioavailability, leading to the development of an experimental guideline, or "Rule-of-oral-PROTACs," to help medicinal chemists improve oral bioavailability.
Article Abstract
Achieving oral bioavailability with Proteolysis Targeting Chimeras (PROTACs) is a key challenge. Here, we report the 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.
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| http://dx.doi.org/10.1021/acs.jmedchem.4c01017 | DOI Listing |
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