Defining optimum lipophilicity and molecular weight ranges for drug candidates-Molecular weight dependent lower logD limits based on permeability.
Analysis of a large, structurally diverse Caco-2 permeability dataset using a variety of statistical techniques suggests that logD and molecular weight are the most important factors in determining the permeability of drug candidates. The limit for logD is shown to be dependent on molecular weight. These limits are shown to be potentially superior to current guidelines in increasing the chances of finding highly permeable compounds. When combined with suggested upper limits for lipophilicity suggested in the literature based on the avoidance of toxicology and other adverse effects, this helps define a lipophilicity range that is optimum for drug candidates.
Waring
Michael J
MJ
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, United Kingdom. mike.j.waring@astrazeneca.com
D000465:Algorithms; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008970:Molecular Weight; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism
D004364:Pharmaceutical Preparations