AI Article Synopsis
- The strategic replacement of hydrogen atoms with fluorine in compounds is used to enhance their potency and alter properties like metabolic stability and pKa.
- The study analyzed a broad dataset to assess how fluorine affects P-glycoprotein mediated efflux, permeability, lipophilicity, and metabolic stability.
- Findings indicate that while incorporating fluorine raises molecular weight, it doesn’t increase P-glycoprotein efflux risk, with fluorine-corrected molecular weight (MWFC) providing a better predictive model.
Article Abstract
Strategic replacement of one or more hydrogen atoms with fluorine atom(s) is a common tactic to improve potency at a given target and/or to modulate parameters such as metabolic stability and pKa. Molecular weight (MW) is a key parameter in design, and incorporation of fluorine is associated with a disproportionate increase in MW considering the van der Waals radius of fluorine versus hydrogen. Herein we examine a large compound data set to understand the effect of introducing fluorine on the risk of encountering P-glycoprotein mediated efflux (as measured by MDR efflux ratio), passive permeability, lipophilicity, and metabolic stability. Statistical modeling of the MDR ER data demonstrated that an increase in MW as a result of introducing fluorine atoms does not lead to higher risk of P-gp mediated efflux. Fluorine-corrected molecular weight (MWFC), where the molecular weight of fluorine has been subtracted, was found to be a more relevant descriptor.
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| http://dx.doi.org/10.1021/acs.jmedchem.6b00027 | DOI Listing |
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