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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.

Authors :
Miller RR
Madeira M
Wood HB
Geissler WM
Raab CE
Martin IJ
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.

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