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Integrating the Impact of Lipophilicity on Potency and Pharmacokinetic Parameters Enables the Use of Diverse Chemical Space during Small Molecule Drug Optimization.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2020 Nov 12; Vol. 63 (21), pp. 12156-12170. Date of Electronic Publication: 2020 Jul 07. - Publication Year :
- 2020
-
Abstract
- Lipophilicity has a dominant effect on many parameters that determine unbound drug exposure as well as drug potency. Despite this, analysis of a large body of drug data indicates lipophilicity has no consistent directional impact on dose. This can be rationalized based on the interplay of the effects of lipophilicity on individual parameter values in pharmacokinetic equations. We believe this undermines the effectiveness of strategies that target specific ranges for drug parameters for which lipophilicity plays such a dominant role. As a result, our research organization no longer leverages the common approach of screening for low intrinsic clearance in vitro to target high unbound exposure in vivo . Instead, we advocate for approaches less biased to lipophilicity through optimization of key parameter ratios controlling dose. We believe this improves efficiency in drug discovery by enabling exploration of broad physicochemical space.
- Subjects :
- Area Under Curve
Blood Proteins chemistry
Blood Proteins metabolism
Drug Design
Half-Life
Humans
Hydrophobic and Hydrophilic Interactions
Pharmaceutical Preparations chemistry
Protein Binding
ROC Curve
Small Molecule Libraries metabolism
Small Molecule Libraries pharmacokinetics
Pharmaceutical Preparations metabolism
Small Molecule Libraries chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 63
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32633947
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.9b01813