Merck

Fluorine in drug design: a case study with fluoroanisoles.

ChemMedChem (2015-03-11)
Li Xing, David C Blakemore, Arjun Narayanan, Ray Unwalla, Frank Lovering, R Aldrin Denny, Huanyu Zhou, Mark E Bunnage
ABSTRACT

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 log D by ~1 log 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 (PhOCF2 H) strikes a better balance of properties with noticeable advantages of log D 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 PhOCF2 H may be a more attractive alternative, and greater exploitation of this motif is recommended.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
1-Octanol, ≥98%, FCC, FG
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Dimethyl sulfoxide, puriss. p.a., ACS reagent, ≥99.9% (GC)
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