Integrating the Impact of Lipophilicity on Potency and Pharmacokinetic Parameters Enables the Use of Diverse Chemical Space during Small Molecule Drug Optimization
- 7 July 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (21), 12156-12170
- https://doi.org/10.1021/acs.jmedchem.9b01813
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.Keywords
This publication has 64 references indexed in Scilit:
- The P-glycoprotein multidrug transporterEssays in Biochemistry, 2011
- Improving Drug Candidates by Design: A Focus on Physicochemical Properties As a Means of Improving Compound Disposition and SafetyChemical Research in Toxicology, 2011
- Principles of early drug discoveryBritish Journal of Pharmacology, 2011
- Xenobiotic Metabolism, Disposition, and Regulation by Receptors: From Biochemical Phenomenon to Predictors of Major ToxicitiesToxicological Sciences, 2010
- Drug efficiency: a new concept to guide lead optimization programs towards the selection of better clinical candidatesExpert Opinion on Drug Discovery, 2010
- The Drug Transporter−Metabolism Alliance: Uncovering and Defining the InterplayMolecular Pharmaceutics, 2009
- Interspecies Prediction of Human Drug Clearance Based on Scaling Data from One or Two Animal SpeciesDrug Metabolism and Disposition, 2007
- Can the pharmaceutical industry reduce attrition rates?Nature Reviews Drug Discovery, 2004
- Quantitative Structure-Activity Relationships of Cytochrome P-450Drug Metabolism Reviews, 1993
- Clinical Pharmacokinetics of FluconazoleClinical Pharmacokinetics, 1993