Premium
Fluorine in Drug Design: A Case Study with Fluoroanisoles
Author(s) -
Xing Li,
Blakemore David C.,
Narayanan Arjun,
Unwalla Ray,
Lovering Frank,
Denny R. Aldrin,
Zhou Huanyu,
Bunnage Mark E.
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402555
Subject(s) - lipophilicity , adme , anisole , chemistry , metabolic stability , drug , stereochemistry , computational chemistry , pharmacology , organic chemistry , biochemistry , in vitro , medicine , catalysis
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.