Fluorine in Drug Design: A Case Study with Fluoroanisoles

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)PhOCF3 increases logD by approximate to 1log unit over PhOCH3 compounds; 2)PhOCF3 shows lower passive permeability despite its higher lipophilicity; and 3)PhOCF3 does not appreciably improve metabolic stability over PhOCH3. Emerging from the investigation, difluoroanisole (PhOCF2H) strikes a better balance of properties with noticeable advantages of logD and transcellular permeability over PhOCF3. Synthetic assessment illustrates that the routes to access difluoroanisoles are often more straightforward than those for trifluoroanisoles. Whereas replacing PhOCH3 with PhOCF3 is a common tactic to optimize ADME properties, our analysis suggests PhOCF2H may be a more attractive alternative, and greater exploitation of this motif is recommended.