Fluorine in Drug Design: A Case Study with Fluoroanisoles

DOI Web Site Web Site 6 Citations

Description

<jats:title>Abstract</jats:title><jats:p>Anisole and fluoroanisoles display distinct conformational preferences, as evident from a survey of their crystal structures. In addition to altering the free ligand conformation, various degrees of fluorination have a strong impact on physicochemical and pharmacokinetic properties. Analysis of anisole and fluoroanisole matched molecular pairs in the Pfizer corporate database reveals interesting trends: 1) PhOCF<jats:sub>3</jats:sub> increases log <jats:italic>D</jats:italic> by ∼1 log unit over PhOCH<jats:sub>3</jats:sub> compounds; 2) PhOCF<jats:sub>3</jats:sub> shows lower passive permeability despite its higher lipophilicity; and 3) PhOCF<jats:sub>3</jats:sub> does not appreciably improve metabolic stability over PhOCH<jats:sub>3</jats:sub>. Emerging from the investigation, difluoroanisole (PhOCF<jats:sub>2</jats:sub>H) strikes a better balance of properties with noticeable advantages of log <jats:italic>D</jats:italic> and transcellular permeability over PhOCF<jats:sub>3</jats:sub>. Synthetic assessment illustrates that the routes to access difluoroanisoles are often more straightforward than those for trifluoroanisoles. Whereas replacing PhOCH<jats:sub>3</jats:sub> with PhOCF<jats:sub>3</jats:sub> is a common tactic to optimize ADME properties, our analysis suggests PhOCF<jats:sub>2</jats:sub>H may be a more attractive alternative, and greater exploitation of this motif is recommended.</jats:p>

Journal

  • ChemMedChem

    ChemMedChem 10 (4), 715-726, 2015-03-06

    Wiley

Citations (6)*help

See more

Report a problem

Back to top