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