title: Fluorination Patterning: A Study of Structural Motifs That Impact Physicochemical Properties of Relevance to Drug Discovery.
abstract: The synthesis of a collection of 3-substituted indole derivatives incorporating partially fluorinated n-propyl and n-butyl groups is described along with an in-depth study of the effects of various fluorination patterns on their properties, such as lipophilicity, aqueous solubility, and metabolic stability. The experimental observations confirm predictions of a marked lipophilicity decrease imparted by a vic-difluoro unit when compared to the gem-difluoro counterparts. The data involving the comparison of the two substitution patterns is expected to benefit molecular design in medicinal chemistry and, more broadly, in life as well as materials sciences.
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich , Vladimir Prelog Weg 3 HCI H335, CH-8093 Zürich, Switzerland.
authors.forename: Quentin A
authors.initials: QA
authors.lastname: Huchet
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Björn
authors.initials: B
authors.lastname: Wagner
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Kratochwil
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Fischer
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kansy
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zimmerli
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich , Vladimir Prelog Weg 3 HCI H335, CH-8093 Zürich, Switzerland.
authors.forename: Erick M
authors.initials: EM
authors.lastname: Carreira
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Klaus
authors.initials: K
authors.lastname: Müller
mesh_terms: D000818:Animals; D001711:Biotransformation; D002627:Chemistry, Physical; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D017611:Fluorine Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D054879:Halogenation; D006801:Humans; D066298:In Vitro Techniques; D008055:Lipids / Q000737:chemistry; D008862:Microsomes, Liver / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D017611:Fluorine Compounds; D008055:Lipids