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A structure-permeability study of small drug-like molecules
Thomas Fichert1, Mehran Yazdanian, John R Proudfoot
1Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
Bioorganic & Medicinal Chemistry Letters
|March 18, 2003
Summary
Highly permeable drug compounds (log D > 0 and < 3) were identified. Unexpectedly, some tetrazole derivatives acted as substrates for drug efflux pumps, impacting drug delivery.
Area of Science:
- Medicinal Chemistry
- Pharmacokinetics
- Drug Discovery
Background:
- Understanding drug permeability is crucial for predicting absorption and distribution.
- Structure-permeability relationships guide the design of effective drug candidates.
- Drug efflux pumps can limit the intracellular concentration of therapeutic agents.
Purpose of the Study:
- To systematically investigate the relationship between molecular structure and permeability in drug-like molecules.
- To identify molecular properties correlating with high permeability.
- To explore potential interactions of diverse chemical functionalities with drug efflux systems.
Main Methods:
- Evaluated a set of small, drug-like molecules across a range of log D values (-2.5 to 3).
- Assessed molecular permeability using established experimental or computational methods.
- Analyzed structure-activity relationships focusing on physicochemical properties and functional groups.
Main Results:
- Compounds with log D values between 0 and 3 demonstrated high permeability.
- A diverse array of functionalities was explored in relation to permeability.
- Several tetrazole-containing compounds were identified as substrates for efflux pumps.
Conclusions:
- The study defines a favorable log D range for high permeability in small molecules.
- The identification of tetrazole derivatives as efflux pump substrates highlights a potential challenge in drug development.
- These findings provide valuable insights for optimizing drug design to enhance permeability and overcome efflux-mediated resistance.