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Probing the links between in vitro potency, ADMET and physicochemical parameters
M Paul Gleeson1, Anne Hersey, Dino Montanari
1The Department of Chemistry, Faculty of Science, Kasetsart University, 50 Phaholyothin Road, Chatuchak, Bangkok 10900, Thailand. paul.gleeson@ku.ac.th
Nature Reviews. Drug Discovery
|March 2, 2011
Summary
High in vitro potency in drug discovery does not guarantee therapeutic success. Analysis of oral drugs reveals that potent compounds often have poor absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, impacting efficacy.
Area of Science:
- Drug Discovery and Development
- Medicinal Chemistry
- Pharmacology
Background:
- Current drug discovery prioritizes high in vitro potency for therapeutic success.
- This strategy may introduce bias in physicochemical properties crucial for drug development.
- The relationship between in vitro potency and desirable ADMET properties is often inverse.
Purpose of the Study:
- To analyze the relationship between in vitro potency and therapeutic dose in oral drugs.
- To investigate the correlation between in vitro potency and ADMET characteristics.
- To re-evaluate the assumption that higher in vitro potency leads to better therapeutics.
Main Methods:
- Analysis of over 500,000 drug discovery and marketed oral drug compounds from the ChEMBL database.
- Statistical examination of in vitro potency, therapeutic dose, and ADMET properties.
- Comparative analysis of potent compounds versus marketed oral drugs.
Main Results:
- Oral drugs rarely exhibit nanomolar potency, with an average around 50 nM.
- Many marketed oral drugs display significant off-target activity.
- In vitro potency shows a weak correlation with the actual therapeutic dose required.
- High in vitro potency is associated with suboptimal ADMET profiles.
Conclusions:
- The emphasis on high in vitro potency in early drug discovery may be counterproductive.
- Poor ADMET properties associated with high potency can negate therapeutic benefits.
- Drug discovery strategies should balance in vitro potency with comprehensive ADMET profiling for successful translation.
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