title: Fluorine in drug design: a case study with fluoroanisoles.
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.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Inc., Cambridge, MA (USA). li.xing@pfizer.com.
authors.forename: Li
authors.initials: L
authors.lastname: Xing
authors.forename: David C
authors.initials: DC
authors.lastname: Blakemore
authors.forename: Arjun
authors.initials: A
authors.lastname: Narayanan
authors.forename: Ray
authors.initials: R
authors.lastname: Unwalla
authors.forename: Frank
authors.initials: F
authors.lastname: Lovering
authors.forename: R Aldrin
authors.initials: RA
authors.lastname: Denny
authors.forename: Huanyu
authors.initials: H
authors.lastname: Zhou
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bunnage
mesh_terms: D000818:Animals; D000840:Anisoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D002460:Cell Line; D004285:Dogs; D015195:Drug Design; D005461:Fluorine / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D054879:Halogenation; D006801:Humans; D008024:Ligands; D008862:Microsomes, Liver / Q000378:metabolism; D010539:Permeability
chemical_list: D000840:Anisoles; D008024:Ligands; D005461:Fluorine
keywords: ADME profiles; anisoles; drug design; fluorination; metabolic stability