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Structural and Physicochemical Features of Oral PROTACs.

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Developing orally available Proteolysis Targeting Chimeras (PROTACs) is difficult. This study introduces a new rule, limiting solvent-exposed H-bond donors (eHBD) to 2, to improve oral PROTAC bioavailability.

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Area of Science:

  • Medicinal Chemistry
  • Pharmacokinetics
  • Drug Discovery

Background:

  • Achieving oral bioavailability for Proteolysis Targeting Chimeras (PROTACs) presents a significant hurdle in drug development.
  • Existing drug development rules may not fully apply to the unique structural characteristics of PROTACs.

Purpose of the Study:

  • To investigate the in vivo pharmacokinetic properties of oral PROTACs in preclinical species.
  • To identify key molecular descriptors that correlate with oral bioavailability in PROTACs.
  • To establish experimental guidelines for designing orally bioavailable PROTACs.

Main Methods:

  • Evaluated pharmacokinetic profiles of four clinical oral PROTACs in mouse, rat, and dog models.
  • Utilized Nuclear Magnetic Resonance (NMR) to determine 3D molecular conformations and preorganization.
  • Introduced and quantified novel descriptors: solvent-exposed hydrogen bond donors (eHBD) and acceptors (eHBA).

Main Results:

  • Established an upper limit of eHBD ≤ 2 for oral PROTACs in apolar environments.
  • Demonstrated greater tolerance for other properties like eHBA, polarity, lipophilicity, and molecular weight compared to traditional oral drugs.
  • Observed significantly lower oral bioavailability in PROTACs with eHBD > 2 compared to those with eHBD ≤ 2 within structurally related series.

Conclusions:

  • Proposed an experimental "Rule-of-oral-PROTACs" to guide medicinal chemists.
  • The eHBD descriptor is critical for achieving oral bioavailability in PROTAC design.
  • This rule provides a practical framework for enhancing oral drug delivery of PROTAC therapeutics.